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1
Kanwar, Gurtej, Anish Kumar, and Anshika Mahajan. "Open source software tools for computer aided drug design." International Journal of Research in Pharmaceutical Sciences 9, no. 1 (March 12, 2018): 86. http://dx.doi.org/10.26452/ijrps.v9i1.1191.
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Computer-aided drug design (CADD) has revolutionized the drug discovery arena and it has reduced the costs associated with finding novel compounds which are having pharmaceutical importance. In CADD, the scientists use the computer software to discover biological active compounds. Molecular docking and energy minimization tools are essential components of structure based drug design. It is a significant tool in structural molecular biology and computer-assisted drug design. It reduces the laboratory workload of the end user and allows researchers to restrict their docking studies to the smallest and the most representative set of macromolecules and small molecules possible. This greatly enhances the productivity of researchers. Energy minimization is an important criterion for selecting a potential 3D molecule. In modeled structures, the 3D structure is affected is due to steric clashes. These clashes happen in a protein structure due to the overlap of non bonding atoms and with the assistance of energy minimization, steric clashes can be eradicated. The open software’s and databases provides a platform for scientists and scholars to carry out their research work in a better way. The docking tools are discussed in this review cover protein-ligand, protein-peptide as well as protein-nucleic acid docking. The tools described include AutoDock 4 and Vina, UCSF DOCK, FLIPDock, EADock, HADDOCK 2.2, SwissDock, PatchDock and ClusPro. In addition to the docking tools, energy minimization tools such as YASARA minimization server, KoBaMIN server and 3D refine server have also been discussed. This mini-review concentrates on open software tools which are free of cost and can be easily downloaded in the computers that are useful for CADD.
Keywords: Molecular docking; Energy minimization; Structure refinement; Drug design; CADD
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Xiao, Wei, Disha Wang, Zihao Shen, Shiliang Li, and Honglin Li. "Multi-Body Interactions in Molecular Docking Program Devised with Key Water Molecules in Protein Binding Sites." Molecules 23, no. 9 (September 11, 2018): 2321. http://dx.doi.org/10.3390/molecules23092321.
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Water molecules play an important role in modeling protein-ligand interactions. However, traditional molecular docking methods often ignore the impact of the water molecules by removing them without any analysis or keeping them as a static part of the proteins or the ligands. Hence, the accuracy of the docking simulations will inevitably be damaged. Here, we introduce a multi-body docking program which incorporates the fixed or the variable number of the key water molecules in protein-ligand docking simulations. The program employed NSGA II, a multi-objective optimization algorithm, to identify the binding poses of the ligand and the key water molecules for a protein. To this end, a force-field-based hydration-specific scoring function was designed to favor estimate the binding affinity considering the key water molecules. The program was evaluated in aspects of the docking accuracy, cross-docking accuracy, and screening efficiency. When the numbers of the key water molecules were treated as fixed-length optimization variables, the docking accuracy of the multi-body docking program achieved a success rate of 80.58% for the best RMSD values for the recruit of the ligands smaller than 2.0 Å. The cross-docking accuracy was investigated on the presence and absence of the key water molecules by four protein targets. The screening efficiency was assessed against those protein targets. Results indicated that the proposed multi-body docking program was with good performance compared with the other programs. On the other side, when the numbers of the key water molecules were treated as variable-length optimization variables, the program obtained comparative performance under the same three evaluation criterions. These results indicated that the multi-body docking with the variable numbers of the water molecules was also efficient. Above all, the multi-body docking program developed in this study was capable of dealing with the problem of the water molecules that explicitly participating in protein-ligand binding.
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Bai, Donglin, and Ao Hong Wang. "Extracellular domains play different roles in gap junction formation and docking compatibility." Biochemical Journal 458, no. 1 (January 20, 2014): 1–10. http://dx.doi.org/10.1042/bj20131162.
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GJ (gap junction) channels mediate direct intercellular communication and play an important role in many physiological processes. Six connexins oligomerize to form a hemichannel and two hemichannels dock together end-to-end to form a GJ channel. Connexin extracellular domains (E1 and E2) have been shown to be important for the docking, but the molecular mechanisms behind the docking and formation of GJ channels are not clear. Recent developments in atomic GJ structure and functional studies on a series of connexin mutants revealed that E1 and E2 are likely to play different roles in the docking. Non-covalent interactions at the docking interface, including hydrogen bonds, are predicted to form between interdocked extracellular domains. Protein sequence alignment analysis on the docking compatible/incompatible connexins indicate that the E1 domain is important for the formation of the GJ channel and the E2 domain is important in the docking compatibility in heterotypic channels. Interestingly, the hydrogen-bond forming or equivalent residues in both E1 and E2 domains are mutational hot spots for connexin-linked human diseases. Understanding the molecular mechanisms of GJ docking can assist us to develop novel strategies in rescuing the disease-linked connexin mutants.
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Worachartcheewan, Apilak, Napat Songtawee, Suphakit Siriwong, Supaluk Prachayasittikul, Chanin Nantasenamat, and Virapong Prachayasittikul. "Rational Design of Colchicine Derivatives as anti-HIV Agents via QSAR and Molecular Docking." Medicinal Chemistry 15, no. 4 (May 20, 2019): 328–40. http://dx.doi.org/10.2174/1573406414666180924163756.
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Background: Human immunodeficiency virus (HIV) is an infective agent that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required. Objective: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly rational design of colchicine and derivatives with anti-HIV activity. Methods: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop the QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking. Results: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross-validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed LOO−CV 2 Q and RMSELOO-CV of 0.7548 and 0.5735 for LOOCV set, and Ext 2 Q of 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed. Conclusion: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents.
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Hamzeh-Mivehroud, Maryam, Zoha Khoshravan-Azar, and Siavoush Dastmalchi. "QSAR and Molecular Docking Studies on Non-Imidazole-Based Histamine H3 Receptor Antagonists." Pharmaceutical Sciences 26, no. 2 (June 27, 2020): 165–74. http://dx.doi.org/10.34172/ps.2019.64.
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Background: In the recent years, histamine H3 receptor (H3R) has been receiving increasing attention in pharmacotherapy of neurological disorders. The aim of the current study was to investigate structural requirements for the prediction of H3 antagonistic activity using quantitative structure-activity relationship (QSAR) and molecular docking techniques. Methods: To this end, genetic algorithm coupled partial least square and stepwise multiple linear regression methods were employed for developing a QSAR model. The obtained QSAR model was stringently assessed using different validation criteria. Results: The generated model indicated that connectivity information and mean absolute charge are two important descriptors for the prediction of H3 antagonistic activity of the studied compounds. To gain insight into the mechanism of interaction between studied molecules and H3R, molecular docking was performed. The most important residues involved in the ligand-receptor interactions were identified. Conclusion: The result of current study can be used for designing of new H3 antagonist and proposing structural modifications to improve H3 inhibitory potency.
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Malinak, David, Eugenie Nepovimova, Daniel Jun, Kamil Musilek, and Kamil Kuca. "Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study." Molecules 23, no. 9 (September 7, 2018): 2291. http://dx.doi.org/10.3390/molecules23092291.
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The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.
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Temelkovski, Damjan, Tamas Kiss, Gabor Terstyanszky, and Pamela Greenwell. "Building Science Gateways for Analysing Molecular Docking Results Using a Generic Framework and Methodology." Journal of Grid Computing 18, no. 3 (July 5, 2020): 529–46. http://dx.doi.org/10.1007/s10723-020-09529-9.
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Abstract Molecular docking and virtual screening experiments require large computational and data resources and high-level user interfaces in the form of science gateways. While science gateways supporting such experiments are relatively common, there is a clearly identified need to design and implement more complex environments for further analysis of docking results. This paper describes a generic framework and a related methodology that supports the efficient development of such environments. The framework is modular enabling the reuse of already existing components. The methodology, which proposes three techniques that the development team can use, is agile and encourages active participation of end-users. Based on the framework and methodology, two prototype implementations of science-gateway-based docking environments are presented and evaluated. The first system recommends a receptor-ligand pair for the next docking experiment, and the second filters docking results based on ligand properties.
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Vazquez-Morado, Luis E., Ramon E. Robles-Zepeda, Adrian Ochoa-Leyva, Aldo A. Arvizu-Flores, Adriana Garibay-Escobar, Francisco Castillo-Yañez, and Alonso A. Lopez-zavala. "Biochemical characterization and inhibition of thermolabile hemolysin from Vibrio parahaemolyticus by phenolic compounds." PeerJ 9 (January 6, 2021): e10506. http://dx.doi.org/10.7717/peerj.10506.
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Vibrio parahaemolyticus (Vp), a typical microorganism inhabiting marine ecosystems, uses pathogenic virulence molecules such as hemolysins to cause bacterial infections of both human and marine animals. The thermolabile hemolysin VpTLH lyses human erythrocytes by a phospholipase B/A2 enzymatic activity in egg-yolk lecithin. However, few studies have been characterized the biochemical properties and the use of VpTLH as a molecular target for natural compounds as an alternative to control Vp infection. Here, we evaluated the biochemical and inhibition parameters of the recombinant VpTLH using enzymatic and hemolytic assays and determined the molecular interactions by in silico docking analysis. The highest enzymatic activity was at pH 8 and 50 °C, and it was inactivated by 20 min at 60 °C with Tm = 50.9 °C. Additionally, the flavonoids quercetin, epigallocatechin gallate, and morin inhibited the VpTLH activity with IC50 values of 4.5 µM, 6.3 µM, and 9.9 µM, respectively; while phenolics acids were not effective inhibitors for this enzyme. Boltzmann and Arrhenius equation analysis indicate that VpTLH is a thermolabile enzyme. The inhibition of both enzymatic and hemolytic activities by flavonoids agrees with molecular docking, suggesting that flavonoids could interact with the active site’s amino acids. Future research is necessary to evaluate the antibacterial activity of flavonoids against Vp in vivo.
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López-López, Edgar, Fernando Prieto-Martínez, and José Medina-Franco. "Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1." Molecules 23, no. 12 (December 11, 2018): 3282. http://dx.doi.org/10.3390/molecules23123282.
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In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.
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Gaffin, Robert D., Kuppan Gokulan, James C. Sacchettini, Timothy E. Hewett, Raisa Klevitsky, Jeffrey Robbins, Vandana Sarin, David C. Zawieja, Gerald A. Meininger, and Mariappan Muthuchamy. "Changes in end-to-end interactions of tropomyosin affect mouse cardiac muscle dynamics." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 2 (August 2006): H552—H563. http://dx.doi.org/10.1152/ajpheart.00688.2005.
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The ends of striated muscle tropomyosin (TM) are integral for thin filament cooperativity, determining the cooperative unit size and regulating the affinity of TM for actin. We hypothesized that altering the α-TM carboxy terminal overlap end to the β-TM counterpart would affect the amino-terminal association, which would alter the end-to-end interactions of TM molecules in the thin filament regulatory strand and affect the mechanisms of cardiac muscle contraction. To test this hypothesis, we generated transgenic (TG) mouse lines that express a mutant form of α-TM in which the first 275 residues are from α-TM and the last nine amino acids are from β-TM (α-TM9aaΔβ). Molecular analyses show that endogenous α-TM mRNA and protein are nearly completely replaced with α-TM9aaΔβ. Working heart preparations data show that the rates of contraction and relaxation are reduced in α-TM9aaΔβ hearts. Left ventricular pressure and time to peak pressure are also reduced (−12% and −13%, respectively). The ratio of maximum to minimum first derivatives of change in left ventricular systolic pressure with respect to time (ratio of +dP/d t to −dP/d t, respectively) is increased, but τ is not changed significantly. Force-intracellular calcium concentration ([Ca2+]i) measurements from intact papillary fibers demonstrate that α-TM9aaΔβ TG fibers produce less force per given [Ca2+]icompared with nontransgenic fibers. Taken together, the data demonstrate that the rate of contraction is primarily affected in TM TG hearts. Protein docking studies show that in the mutant molecule, the overall carbon backbone is perturbed about 1.5 Å, indicating that end-to-end interactions are altered. These results demonstrate that the localized flexibility present in the coiled-coil structures of TM isoforms is different, and that plays an important role in interacting with neighboring thin filament regulatory proteins and with differentially modulating the myofilament activation processes.
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Moriev, R., O. Vasylchenko, M. Platonov, O. Grygorenko, K. Volkova, and S. Zozulya. "Identification of Novel IGF1R Kinase Inhibitors by Molecular Modeling and High-Throughput Screening." Acta Naturae 5, no. 2 (June 15, 2013): 90–99. http://dx.doi.org/10.32607/20758251-2013-5-2-90-99.
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The aim of this study was to identify small molecule compounds that inhibit the kinase activity of the IGF1 receptor and represent novel chemical scaffolds, which can be potentially exploited to develop drug candidates that are superior to the existing experimental anti-IGF1R therapeuticals. To this end, targeted compound libraries were produced by virtual screening using molecular modeling and docking strategies, as well as the ligand-based pharmacophore model. High-throughput screening of the resulting compound sets in a biochemical kinase inhibition assay allowed us to identify several novel chemotypes that represent attractive starting points for the development of advanced IGF1R inhibitory compounds.
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Czeleń, Przemysław, and Beata Szefler. "The Oxindole Derivatives, New Promising GSK-3β Inhibitors as One of the Potential Treatments for Alzheimer’s Disease—A Molecular Dynamics Approach." Biology 10, no. 4 (April 15, 2021): 332. http://dx.doi.org/10.3390/biology10040332.
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The glycogen synthase kinase 3β (GSK-3β) is a protein kinase involved in regulating numerous physiological processes such as embryonic development, transcription, insulin action, cell division cycle and multiple neuronal functions. The overexpression of this enzyme is related to many diseases such as schizophrenia, Alzheimer’s disease, diabetes and cancer. One of the basic methods of treatment in these cases is the usage of ATP-competitive inhibitors. A significant group of such compounds are indirubin and its analogs, e.g., oxindole derivatives. The compounds considered in this work are 112 newly designed oxindole derivatives. In the first stage, such molecular properties of considered compounds as toxicity and LogP were estimated. The preliminary analysis of the binding capabilities of considered compounds towards the GSK-3β active site was conducted with the use of the docking procedure. Based on obtained molecular properties and docking simulations, a selected group of complexes that were analyzed in the molecular dynamics stage was nominated. The proposed procedure allowed for the identification of compounds such as Oxind_4_9 and Oxind_13_10, which create stable complexes with GSK-3β enzyme and are characterized by the highest values of binding affinity. The key interactions responsible for stabilization of considered ligand–protein complexes were identified, and their dynamic stability was also determined. Comparative analysis including analyzed compounds and reference molecule 3a, which is also an oxindole derivative with a confirmed inhibitory potential towards GSK3B protein, clearly indicates that the proposed compounds exhibit an analogous binding mechanism, and the obtained binding enthalpy values indicate a slightly higher binding potential than the reference molecule.
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Fatmawaty, Fatmawaty, Muhammad Hanafi, Rosmalena Rosmalena, and Vivitri Dewi Prasasty. "SKRINING IN SILICO POTENSI SENYAWA ALLICIN DARI ALLIUM SATIVUM SEBAGAI ANTIPLASMODIUM." Jurnal Kimia Terapan Indonesia 17, no. 2 (December 10, 2015): 175–84. http://dx.doi.org/10.14203/jkti.v17i2.33.
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Allicin compound (2-propene-1- sulphinothioat acid S-2-propenyl ester) is known to have potential as antiplasmodium in vitro. However, the inhibitory activity mechanism of Allicin to plasmodium is still unknown. In this research, we determined the inhibitory activity of Allicin in silico. Identification of physicochemical properties of Allicin compound and two Allicin derivatives, Alc1, Alc2 and Ac2Alc3 were also conducted.. Furthermore, analysis of drug-likeness and adsorption-distribution-metabolism-excretion (ADME) were carried out on the Allicin compound and its derivatives to find the potential of these compounds as drug candidates. In determining the specific interaction, we utilized molecular docking analysis between Allicin and its derivatives against a protein target Cysteine Protease (SP). Molecular docking results showed that Allicin derivative, Alc2 (S-prop-2-en-1-yl 3-methylbut-2-ene-1-sulfinothioate, C10H18OS2) has better potential as inhibitors than Allicin, based on the lower bond energies and the inhibition constants, thus Alc2 can be used as an antiplasmodium agent candidate.Keywords: Allicin, Allicin derivatives, drug likeness, ADME, molecular docking
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Khan, Azhar U., Mahboob Alam, Soonheum Park, Poonam Dwivedi, Sunil K. Sharma, and Sapna Jain. "Synthesis, Antibacterial Activity and Molecular Docking of Phospholidinones in Stigmastane Series." Current Computer-Aided Drug Design 15, no. 3 (April 10, 2019): 259–64. http://dx.doi.org/10.2174/1573409914666181029122448.
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<P>Introduction: Steroid compounds are widely distributed in nature throughout scientific history. Living organisms such as animals and vegetables have steroids that show a significant effect on their vital activities. Sterols are key components of all eukaryotic cell membranes. Methods: Steroidal compounds; 3β-oxo-[1’,3’,2’-oxathiaphos-phalidine-2’-one] stigmast-5-ene and 3β- oxo[1`,3`,2`-dioxaphosphalidine-2`-one]-stigmast-5-ene were successfully prepared using easily accessible 3β-hydroxy stigmast-5-ene with phosphorous oxychloride (POCl3), 2- mercaptoethanol/ethylene glycol and triethylamine (Et3N) in dry diethyl ether. Products were obtained in semi-solid state and characterized using physicochemical techniques. Results: The results of the bioassay showed that the synthesized compound containing the sulfur atom had antibacterial activity. Molecular docking was also done in order to show in silico antibacterial activity and to make out the probable binding mode of compound with the amino acid residues of protein. Conclusion: The results of the docking study showed that synthesized compound 2 had minimal binding energy with substantial affinity for the active site.</P>
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Magkrioti, Christiana, Eleanna Kaffe, Elli-Anna Stylianaki, Camelia Sidahmet, Georgia Melagraki, Antreas Afantitis, Alexios N. Matralis, and Vassilis Aidinis. "Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors." International Journal of Molecular Sciences 21, no. 19 (September 23, 2020): 7002. http://dx.doi.org/10.3390/ijms21197002.
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Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.
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Mak, Ho Yi, Sue Hoare, Pirkko M. A. Henttu, and Malcolm G. Parker. "Molecular Determinants of the Estrogen Receptor-Coactivator Interface." Molecular and Cellular Biology 19, no. 5 (May 1, 1999): 3895–903. http://dx.doi.org/10.1128/mcb.19.5.3895.
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ABSTRACT Transcriptional activation by the estrogen receptor is mediated through its interaction with coactivator proteins upon ligand binding. By systematic mutagenesis, we have identified a group of conserved hydrophobic residues in the ligand binding domain that are required for binding the p160 family of coactivators. Together with helix 12 and lysine 366 at the C-terminal end of helix 3, they form a hydrophobic groove that accommodates an LXXLL motif, which is essential for mediating coactivator binding to the receptor. Furthermore, we demonstrated that the high-affinity binding of motif 2, conserved in the p160 family, is due to the presence of three basic residues N terminal to the core LXXLL motif. The recruitment of p160 coactivators to the estrogen receptor is therefore likely to depend not only on the LXXLL motif making hydrophobic interactions with the docking surface on the receptor, but also on adjacent basic residues, which may be involved in the recognition of charged residues on the receptor to allow the initial docking of the motif.
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Vadivelu, Annapoorna. "Molecular docking studies of 1,3,4 -thiadiazoles as myeloperoxidase inhibitors." Journal of Pharmaceutical and Biological Sciences 9, no. 1 (July 15, 2021): 63–69. http://dx.doi.org/10.18231/j.jpbs.2021.008.
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Myeloperoxidase (MPO) is a heterodimeric, cationic and glycosylated haeme enzyme which gets released under increased oxidative stress producing neutrophil oxidant, hypochlorous acid having the capacity to modify various biomolecules by chlorination and/or oxidation of sulfhydryl groups in proteins causing their inactivation and promoting inflammatory tissue damage. Different levels of hypochlorus acid are used as a trait marker for prescribing the disorders e.g. atherosclerosis, rheumatoid arthritis, lung cancer, Immuno-reactivity. Mini library of 22500 2,5disubstituted 1,3,4 thiadiazoles were docked with Myeloperoxidase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking process. Keeping this fact in view, critical evaluation of the performance was performed by GLIDE by HTVS, SP and XP. The ADME parameters by QIKPROP and protein-ligand binding free energies were calculated using the Prime/MM-GBSA module of Schrödinger.Both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and core influence the target site through prominent hydrophobic and charged interaction with the backbone and side chain residues in the target site that improves the affinity of the molecule. The compound selected as potent inhibitor is having minimum binding affinity, maximum GScore and minimum FlexX energy. The amino acids residues ASP98, ASP94, THR100 and GLU 102 in the MPO gene domain active site form hydrogen bonds with the ligand. Compounds 3350-5150 showed better interaction with haeme enzyme for further understanding of structures, reliability and Biomolecularactivityy in connection with oxidative stress induced disorders.
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Shi, Xiaoqing, Haosheng Zhang, Yue Hu, Xiaochen Li, Songjiang Yin, Runlin Xing, Nongshan Zhang, Jun Mao, and Peimin Wang. "Mechanism of Salviae Miltiorrhizae Radix et Rhizoma in the Treatment of Knee Osteoarthritis Based on Network Pharmacology." Natural Product Communications 15, no. 12 (December 2020): 1934578X2098313. http://dx.doi.org/10.1177/1934578x20983130.
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Objective The molecular mechanism of Salviae Miltiorrhizae Radix et Rhizoma (SMRR) in the treatment of knee osteoarthritis (KOA) was analyzed based on network pharmacology. Methods Active components and potential targets of SMRR were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. KOA targets were obtained from the OMIM, DisGeNET, DrugBank, PharmGKB, and GeneCards Databases. The potential targets of SMRR in the treatment of KOA were identified by the Venn diagram. A protein-protein interaction network was generated with the STRING database. Visualization of the interactions in a potential pharmacodynamic component-target network was accomplished with Cytoscape software. The Database for Annotation, Visualization, and Integrated Discovery database and R software were used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway annotation analyses of common targets. Molecular docking of the potential leading components, as determined by efficacy with the core target molecules, was performed with Discovery Studio. Results Fifty-seven potential pharmacodynamic components and 58 potential targets of SMRR in the treatment of KOA were found. Bioinformatics analyses showed that the interleukin (IL)-17, hypoxia-inducible factor-1 (HIF-1), and tumor necrosis factor (TNF) signaling pathways, as well as the advanced glycation end product-receptor for advanced glycation end product signaling pathway in cases of diabetic complications, are related to the molecular mechanism of SMRR in the treatment of KOA. Molecular docking results showed that luteolin, tanshinone IIA, cryptotanshinone, and other components of SMRR had a strong affinity for MYC, signal transducer and activator of transcription 3, caspase-3 (CASP3), JUN, cyclin D1, prostaglandin endoperoxide synthase 2 (PTGS2), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), protein kinase B, vascular endothelial growth factor A, and other targets. Conclusion SMRR indirectly regulates IL-17, HIF-1, TNF, and other signal transduction pathways by regulating the expression of proteins, including PTGS2, MAPK1, EGFR, and CASP3, thus playing a role in promoting chondrocyte proliferation, improving microcirculation, eliminating free radicals, and inhibiting inflammatory factors.
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Selvaraj, Revathy, J. Suresh, and A. Arun. "Cyanuric Chloride Containing Chalcones for Possible Breast Cancer Treatment: Synthesis, Antimicrobial and in silico Screening." Asian Journal of Chemistry 32, no. 2 (December 30, 2019): 408–14. http://dx.doi.org/10.14233/ajchem.2020.22461.
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In this work, we have synthesized efficient antibacterial compounds with anticancer novel molecules based on cyanuric chloride containing chalcone moiety. For this, novel triazine-based organic molecules were synthesized by using cyanuric chloride and 2,4-dichloro-1-ene(4-hydroxyphenyl)phenone and characterized by elemental analysis, FT-IR, NMR and UV-visible spectrometry techniques. Melting point of the molecules were increased with an increase in substitution on cyanuric chloride. The minimum inhibitory concentration (MIC) value of the synthesized compounds showed an excellent result on Gram-negative bacteria with low MIC value of 1.95 μg/mL. Gram-positive bacteria showed little resistance to the synthesized drug. The synthesized compounds were tested for their use as an anticancer drug using in silico screening method. The synthesized compounds in silico molecular docking method using breast cancer protein (BRCA2) confirms that triazine derivative with all three chlorine molecules replaced by 2,4-dichloro-1-ene(4-hydroxyphenyl)phenone showed highest binding energy with the value of -9.1900 Kcal/mol which is in agreement with the observed high MIC value obtained for Gram-negative bacteria. The synthesized molecules preferentially targeted the topoisomerase II of the bacteria. Overall, an efficient antimicrobial drug is synthesized using a simple preparation method.
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Orduz Díaz, Luisa, Freddy Bernal, and Ericsson Coy Barrera. "Diterpenos de Núcleo Kaurano como Inhibidores de la PTR1 de Leishmania: un Estudio In-Silico." Revista Facultad de Ciencias Básicas 9, no. 1 (June 10, 2013): 142. http://dx.doi.org/10.18359/rfcb.362.
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<p>La pteridina reductasa-1 (PTR1) ha sido descubierta como la responsable de la reducción de la susceptibilidad a antifolatos (e.g., metotrexato) de parásitos tripanosómicos, lo cual la ha convertido en un objetivo quimioterapeútico. Por esta razón, trece diterpenos conocidos, de núcleo kaurano, fueron evaluados <em>in silico </em>contra la PTR1, mediante docking molecular y modelamiento farmacofórico. El docking molecular mostró claras interacciones polares con algunos residuos del sitio activo de la PTR1, que dependieron principalmente de la presencia de un grupo carboxilo en C19. Estos resultados fueron corroborados por el mapeo de interacciones residuales, indicando que los ácidos kauren-19-oicos poseen las características estructurales importantes para una inhibición de la PTR1, lo cual es un excelente punto de partida para futuros estudios de optimización estructural de este tipo de compuestos.</p>
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Guerrini, Marco, Stefano Elli, Pierre Mourier, Timothy R. Rudd, Davide Gaudesi, Benito Casu, Christian Boudier, Giangiacomo Torri, and Christian Viskov. "An unusual antithrombin-binding heparin octasaccharide with an additional 3-O-sulfated glucosamine in the active pentasaccharide sequence." Biochemical Journal 449, no. 2 (December 14, 2012): 343–51. http://dx.doi.org/10.1042/bj20121309.
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The 3-O-sulfation of N-sulfated glucosamine is the last event in the biosynthesis of heparin/heparan sulfate, giving rise to the antithrombin-binding pentasaccharide sequence AGA*IA, which is largely associated with the antithrombotic activity of these molecules. The aim of the present study was the structural and biochemical characterization of a previously unreported AGA*IA*-containing octasaccharide isolated from the very-low-molecular-mass heparin semuloparin, in which both glucosamine residues of the pentasaccharide moiety located at the non-reducing end bear 3-O-sulfate groups. Two-dimensional and STD (saturation transfer difference) NMR experiments clearly confirmed its structure and identified its ligand epitope binding to antithrombin. The molecular conformation of the octasaccharide–antithrombin complex has been determined by NMR experiments and docking/energy minimization. The presence of the second 3-O-sulfated glucosamine in the octasaccharide induced more than one order of magnitude increase in affinity to antithrombin compared to the pentasaccharide AGA*IA.
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Wu, Zhulin, Li He, Lianan Wang, and Lisheng Peng. "Systematically Exploring the Antitumor Mechanisms of Core Chinese Herbs on Hepatocellular Carcinoma: A Computational Study." Evidence-Based Complementary and Alternative Medicine 2020 (September 15, 2020): 1–13. http://dx.doi.org/10.1155/2020/2396569.
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Objective. Chinese herbs play a positive role in the management of hepatocellular carcinoma (HCC) in China. However, it is not clear which of Chinese herbs are critical for the treatment of HCC. Besides, mechanisms of CCHs in the treatment of HCC remain unclear. Hence, our goal is to identify the core Chinese herbs (CCHs) for treating HCC and explore their antitumor mechanism. Methods. Firstly, clinical traditional Chinese medicine (TCM) prescriptions for HCC were collected from Chinese National Knowledge Infrastructure (CNKI) database, and then, data mining software was used to identify CCHs. After that, bioactive compounds and corresponding target genes of CCHs were obtained using three TCM databases, and target genes of HCC were acquired from MalaCards and OMIM. Subsequently, common target genes of CCHs and HCC were screened. Moreover, biological functions and pathways were analyzed, and Cytoscape plugin cytoHubba was used to identify hub genes. Finally, prognostic values of hub genes were verified by survival analysis, and the molecular docking approach was utilized to validate the interactions between targets and bioactive compounds of CCHs. Results. Eight CCHs were determined from 630 prescriptions, and 100 bioactive compounds (e.g., quercetin and luteolin) and 126 common target genes were screened. Furthermore, common target genes of CCHs and HCC were mainly enriched in cancer-associated pathways, and six hub genes with statistical significance in survival analysis were selected as key target genes for molecular docking. Additionally, molecular docking showed that the bioactive compounds docked well with the protein receptors of key target genes. Conclusion. By combining data mining, network pharmacology, molecular docking, and survival analysis methods, we found that CCHs may play a therapeutic role in HCC through regulating the target genes and pathways related to cancer occurrence and development, angiogenesis, metastasis, and prognosis.
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Al Musayeib, Nawal M., Musarat Amina, Gadah Abdulaziz Al-Hamoud, Gamal A. Mohamed, Sabrin R. M. Ibrahim, and Samah Shabana. "Plectrabarbene, a New Abietane Diterpene from Plectranthus barbatus Aerial Parts." Molecules 25, no. 10 (May 20, 2020): 2365. http://dx.doi.org/10.3390/molecules25102365.
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A new abietane diterpene namely plectrabarbene (2), together with two known compounds: sugiol (1) and 11,14-dihydroxy-8,11,13-abietatrien-7-one (3) have been isolated from the aerial parts of Plectranthus barbatus Andr. (Labiatae). The structures of these compounds were determined by various spectral techniques (e.g., UV, IR, NMR, and FAB) and by comparison with the literature data. A molecular docking study of the isolated diterpenes (1–3) was performed with AChE to gain an insight into their AChE inhibition mechanism. The results of docking experiments revealed that the all tested compounds showed binding affinity at the active site of AchE in comparison to donepezil.
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Arcon, Juan Pablo, Carlos P. Modenutti, Demian Avendaño, Elias D. Lopez, Lucas A. Defelipe, Francesca Alessandra Ambrosio, Adrian G. Turjanski, Stefano Forli, and Marcelo A. Marti. "AutoDock Bias: improving binding mode prediction and virtual screening using known protein–ligand interactions." Bioinformatics 35, no. 19 (March 2, 2019): 3836–38. http://dx.doi.org/10.1093/bioinformatics/btz152.
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Abstract Summary The performance of docking calculations can be improved by tuning parameters for the system of interest, e.g. biasing the results towards the formation of relevant protein–ligand interactions, such as known ligand pharmacophore or interaction sites derived from cosolvent molecular dynamics. AutoDock Bias is a straightforward and easy to use script-based method that allows the introduction of different types of user-defined biases for fine-tuning AutoDock4 docking calculations. Availability and implementation AutoDock Bias is distributed with MGLTools (since version 1.5.7), and freely available on the web at http://ccsb.scripps.edu/mgltools/ or http://autodockbias.wordpress.com. Supplementary information Supplementary data are available at Bioinformatics online.
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Chakraborti, Sajal, Jaganmay Sarkar, Rajabrata Bhuyan, and Tapati Chakraborti. "Role of catechins on ET-1-induced stimulation of PLD and NADPH oxidase activities in pulmonary smooth muscle cells: determination of the probable mechanism by molecular docking studies." Biochemistry and Cell Biology 96, no. 4 (August 2018): 417–32. http://dx.doi.org/10.1139/bcb-2017-0179.
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The treatment of human pulmonary artery smooth muscle cells with ET-1 stimulates the activity of PLD and NADPH oxidase, but this stimulation is inhibited by pretreatment with bosentan (ET-1 receptor antagonist), FIPI (PLD inhibitor), apocynin (NADPH oxidase inhibitor), and EGCG and ECG (catechins having a galloyl group), but not EGC and EC (catechins devoid of a galloyl group). Herein, using molecular docking analyses based on our biochemical studies, we determined the probable mechanism by which the catechins containing a galloyl group inhibit the stimulation of PLD activity induced by ET-1. The ET-1-induced stimulation of PLD activity was inhibited by SecinH3 (inhibitor of cytohesin). Arf6 and cytohesin-1 are associated in the cell membrane, which is not inhibited by the catechins during ET-1 treatment of the cells. However, EGCG and ECG inhibited the binding of GTPγS with Arf6, even in the presence of cytohesin-1. The molecular docking analyses revealed that the catechins containing a galloyl group (EGCG and ECG) with cytohesin-1–Arf6GDP, but not the catechins without a galloyl group (EGC and EC), prevent GDP–GTP exchange in Arf6, which seems to be an important mechanism for inhibiting the activation of PLD induced by ET-1, and subsequently increases the activity of NADPH oxidase.
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Ahmed, H. A., and I. Y. Alkali. "In silico molecular docking studies of some phytochemicals against peroxisome-proliferator activated receptor gamma (PPAR-γ)." GSC Biological and Pharmaceutical Sciences 5, no. 2 (November 30, 2018): 001–5. http://dx.doi.org/10.30574/gscbps.2018.5.2.0085.
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Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that regulate the gene expression of proteins involved in glucose, lipid metabolism, adipocyte proliferation and differentiation and insulin sensitivity. Thiazolidinediones (TZDs) are one important class of synthetic agonists of PPAR-γ. TZDs are antidiabetic agents that target adipose tissue and improve insulin sensitivity, and they are currently being used in the treatment of type 2 diabetes. The study was carried out in order to discover new phytochemicals that have the ability to stimulate the PPAR-γ using molecular docking studies. AutoDock vina was used as molecular-docking tool in order to carry out the docking simulations. Nine phytochemicals namely plumbagin, quercetin, isovitexin, mangiferin, syringin, lupe-20-ene-3-one, purine 2, 6-dione, diosmetin and β sitosterol and pioglitazone a standard drug were docked against PPAR-γ using AutoDock vina and the results were analyzed using binding affinity. The results revealed that the compounds have significant binding affinity towards the PPAR-γ comparable to pioglitazone the standard drug. Based on the findings of this study these phytochemicals can serve as source of antidiabetic drugs via the mechanism of inhibition of PPAR-γ.
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S, Hemalatha, and Fazeela Mahaboob Begum. "CHARACTERISATION, IN SILICO AND IN VITRO DETERMINATION OF ANTIDIABETIC AND ANTI INFLAMMATORY POTENTIAL OF ETHANOLIC EXTRACT OF SARGASSUM WIGHTII." Asian Journal of Pharmaceutical and Clinical Research 10, no. 4 (April 1, 2017): 297. http://dx.doi.org/10.22159/ajpcr.2017.v10i4.16742.
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Objective: The current study was intended to investigate and characterize the phytoconstituents of Sargassum wightii ,evaluate its anti diabetic and anti inflammatory potential under in silico and in vitro conditions.Methods: The marine algae S.wightii was extracted with ethanol. The ethanolic extract was screened for various phytoconstituents, quantified for total flavonoid and polyphenol content. FTIR and Mass spectrometry was used for characterizing the ethanolic extract. Antidiabetic potential of the phytoconstituents was analysed by molecular docking and enzyme inhibition assays. The anti inflammatory potential was evaluated by albumin denaturation assay.Results: The phytochemical screening revealed the presence of flavonoids, polyphenols, alkaloids, tannins, carbohydrates, proteins, oils and fat present in the ethanol extract. The FTIR analysis showed the presence of α,b unsaturated ketone, alcohol and ether groups in the extract. MS analysis identified l - (+) - Ascorbic acid 2, 6 dihexadeconoate and Dotriacontyl isopropyl ether in the ethanolic extract. The molecular docking studies revealed that l - (+) - Ascorbic acid 2, 6 dihexadeconoate interacted with both α amylase and α glucosidase with a consensus score of 5.The results of in vitro analysis showed that the ethanolic extract exhibited strong inhibitory activity on α amylase (IC 50 8mg/ml) and α glucosidase (IC 50 6mg/ml) respectively. The ethanolic extract also inhibited the formation of advanced glycation end products (IC 50 10mg/ml).Further the ethanolic extract inhibited the denaturation of albumin (IC 50 2.5 mg/ml) there by revealing the anti inflammatory potential of S.wightii.Conclusion: Hence it can be concluded that S.wightii possess anti diabetic and anti inflammatory potential which may be due to the presence of l - (+) - Ascorbic acid 2, 6 dihexadeconoate and flavonoids, polyphenols, alkaloids, tannins, carbohydrates, proteins, oils and fat present in the extract.Key words: Sargassum wightii, α amylase, α glucosidase, advanced glycation end products, molecular docking.
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Barua, Harsh, Nidhi Bhagat, and (mrs ). M. P. Toraskar. "STUDY OF BINDING INTERACTIONS OF HUMAN CARBONIC ANHYDRASE XII." International Journal of Current Pharmaceutical Research 9, no. 1 (December 31, 2016): 118. http://dx.doi.org/10.22159/ijcpr.2017v9i1.16633.
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Objective: The present study was carried out to study the binding interactions of different N’-(substituted phenyl sulfonyl)-pyridine-2-carbohydrazide derivatives and N’-(substituted phenyl sulfonyl)-thiophene-2-carbohydrazide derivatives which were synthesized by senior students from research laboratory, with objective to explore the suitability of selected ligands for their binding affinity for the selected target.Methods: Binding interactions of the selected ligands were studied using glide module of Schrodinger software using Maestro 10.1 interface. At the end of molecular docking studies, docking scores along with 2D and 3D binding interactions of these ligands were studied to evaluate the potency of ligands to act as selective human carbonic anhydrase (hCAXII) inhibitors in comparison with standard inhibitor Acetazolamide (AZA).Results: Docking study on the ligands exhibited very similar conformation and binding interactions with hCAXII as that of standard. This suggests that selected ligands might possess significant binding affinity for hCAXII.Conclusion: It can be concluded that the selected ligands have the potential to act as inhibitors of hCAXII.
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Prabahar, Archana, Subashini Swaminathan, Arul Loganathan, and Ramalingam Jegadeesan. "Identification of Novel Inhibitors for Tobacco Mosaic Virus Infection in Solanaceae Plants." Advances in Bioinformatics 2015 (October 18, 2015): 1–9. http://dx.doi.org/10.1155/2015/198214.
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Tobacco mosaic virus (TMV) infects several crops of economic importance (e.g., tomato) and remains as one of the major concerns to the farmers. TMV enters the host cell and produces the capping enzyme RNA polymerase. The viral genome replicates further to produce multiple mRNAs which encodes several proteins, including the coat protein and an RNA-dependent RNA polymerase (RdRp), as well as the movement protein. TMV replicase domain was chosen for the virtual screening studies against small molecules derived from ligand databases such as PubChem and ChemBank. Catalytic sites of the RdRp domain were identified and subjected to docking analysis with screened ligands derived from virtual screening LigandFit. Small molecules that interact with the target molecule at the catalytic domain region amino acids, GDD, were chosen as the best inhibitors for controlling the TMV replicase activity.
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Díaz, Katy, Luis Espinoza, Rodrigo Carvajal, Marcos Conde-González, Vladimir Niebla, Andrés F. Olea, and Yamilet Coll. "Biological Activities and Molecular Docking of Brassinosteroids 24-Norcholane Type Analogs." International Journal of Molecular Sciences 21, no. 5 (March 6, 2020): 1832. http://dx.doi.org/10.3390/ijms21051832.
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The quest and design of new brassinosteroids analogs is a matter of current interest. Herein, the effect of short alkyl side chains and the configuration at C22 on the growth-promoting activity of a series of new brassinosteroid 24-norcholan-type analogs have been evaluated by the rice leaf inclination test using brassinolide as positive control. The highest activities were found for triol 3 with a C22(S) configuration and monobenzoylated derivatives. A docking study of these compounds into the active site of the Brassinosteroid Insensitive 1(BRI1)–ligand–BRI1-Associated Receptor Kinase 1 (BAK1) complex was performed using AutoDock Vina, and protein–ligand contacts were analyzed using LigPlot+. The results suggest that the hydrophobic interactions of ligands with the receptor BRI1LRR and hydrogen bonding with BAK1 in the complex are important for ligand recognition. For monobenzoylated derivatives, the absence of the hydrophobic end in the alkyl chain seems to be compensated by the benzoyl group. Thus, it would be interesting to determine if this result depends on the nature of the substituent group. Finally, mixtures of S/R triols 3/4 exhibit activities that are comparable or even better than those found for brassinolide. Thus, these compounds are potential candidates for application in agriculture to improve the growth and yield of plants against various types of biotic and abiotic stress.
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Zhao, Hongchuan, Pu Sun, Wei Guo, Yi Wang, Ao Zhang, Linghua Meng, and Chunyong Ding. "Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO-1) Inhibitors Based on Ortho-Naphthaquinone-Containing Natural Product." Molecules 24, no. 6 (March 18, 2019): 1059. http://dx.doi.org/10.3390/molecules24061059.
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There is great interest in developing small molecules agents capable of reversing tumor immune escape to restore the body’s immune system. As an immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO-1) is considered a promising target for oncology immunotherapy. Currently, none of IDO-1 inhibitors have been launched for clinical practice yet. Thus, the discovery of new IDO-1 inhibitors is still in great demand. Herein, a series of diverse ortho-naphthaquinone containing natural product derivatives were synthesized as novel IDO-1 inhibitors. Among them, 1-ene-3-ketone-17-hydroxyl derivative 12 exhibited significantly improved enzymatic and cellular inhibitory activity against IDO-1 when compared to initial lead compounds. Besides, the molecular docking study disclosed that the two most potent compounds 11 and 12 have more interactions within the binding pocket of IDO-1 via hydrogen-bonding, which may account for their higher IDO-1 inhibitory activity.
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Ali, Meer Asif, Sugunakar Vuree, Himshikha Goud, Tajamul Hussain, Anuraj Nayarisseri, and Sanjeev Kumar Singh. "Identification of High-affinity Small Molecules Targeting Gamma Secretase for the Treatment of Alzheimer’s Disease." Current Topics in Medicinal Chemistry 19, no. 13 (August 27, 2019): 1173–87. http://dx.doi.org/10.2174/1568026619666190617155326.
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Background: Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The main component of the plaques being amyloid-beta (Aβ42) results from the sequential cleavage of Amyloid precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI). Methods: A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking. The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain similar compounds. The generated compounds were docked again at the same docking site on the protein to find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments for both the compounds, obtained from the two aforesaid docking studies, which included interaction energy descriptors, ADMET profiling and PreADMET evaluations. Results: 111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915 (CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds, electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand Descriptor values were nearly equivalent. Conclusion: These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in vitro pharmacokinetic and dynamic studies.
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LIU, JUNXING, ZHIWEI YANG, SHUQIU WANG, LEI LIU, GUANG CHEN, and LIN WANG. "EXPLORING THE MOLECULAR BASIS OF H5N1 HEMAGGLUTININ BINDING WITH CATECHINS IN GREEN TEA: A FLEXIBLE DOCKING AND MOLECULAR DYNAMICS STUDY." Journal of Theoretical and Computational Chemistry 11, no. 01 (February 2012): 111–25. http://dx.doi.org/10.1142/s0219633612500071.
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The influenza A (H5N1) virus attracts a worldwide attention and calls for the urgent development of novel antiviral drugs. In this study, explicitly solvated flexible docking and molecular dynamics (MD) simulations were used to study the interactions between the H5N1 sub-type hemagglutinin (HA) and various catechin compounds, including EC ([–]-epicatechin), EGC ([–]-epigallocatechin), ECG ([–]-epicatechin gallate) and EGCG ([–]-epigallocatechin gallate). The four compounds have respective binding specificities and their interaction energies with HA decrease in the order of EGCG (-133.52) > ECG (-111.11) > EGC (-97.94) > EC (-83.39). Units in kcal mol-1. Residues IleA267, LysA269, ArgB68 and GluB78 play important roles during all the binding processes. EGCG has the best bioactivity and shows potential as a lead compound. Besides, the importance was clarified for the functional groups it was revealed that the C5′ hydroxyl and trihydroxybenzoic acid groups are crucial for the catechin inhibitory activities, especially the latter. Combined with the structural and property analyses, this work also proposed the way to effectively modify the functional groups of EGCG. The experimental efforts are expected in order to actualize the catechin derivatives as novel anti-influenza agents in the near future.
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Chen, Jui-Le, Chun-Wei Tsai, Ming-Chao Chiang, and Chu-Sing Yang. "A High Performance Cloud-Based Protein-Ligand Docking Prediction Algorithm." BioMed Research International 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/909717.
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The potential of predicting druggability for a particular disease by integrating biological and computer science technologies has witnessed success in recent years. Although the computer science technologies can be used to reduce the costs of the pharmaceutical research, the computation time of the structure-based protein-ligand docking prediction is still unsatisfied until now. Hence, in this paper, a novel docking prediction algorithm, named fast cloud-based protein-ligand docking prediction algorithm (FCPLDPA), is presented to accelerate the docking prediction algorithm. The proposed algorithm works by leveraging two high-performance operators: (1) thenovelmigration (information exchange) operator is designed specially for cloud-based environments to reduce the computation time; (2) theefficientoperator is aimed at filtering out the worst search directions. Our simulation results illustrate that the proposed method outperforms the other docking algorithms compared in this paper in terms of both the computation time and the quality of the end result.
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Niazi, Sarfaraj, Vishwamohana M. Hebbar, Pooja Mathew, Raj K. D. Kumar, and Madhusudan Purohit. "Exploration of Angiotensin II Type 1 Receptor Modulators by Molecular Fingerprints and Docking Simulations." Letters in Drug Design & Discovery 15, no. 1 (January 3, 2018): 95–102. http://dx.doi.org/10.2174/1570180814666170605121418.
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Background: Overexpression of Angiotensin Type 1 (AT1) receptor along with other deregulated oncogenic factors, for e.g. Vascular Endothelial Growth Factor (VEGF) triggers angiogenesis, which is one of the hallmarks of cancer. AT1 receptor, being a key component of the renin - angiotensin system (RAS), also helps in the regulation of blood pressure. In the present study, we report on the identification of novel Angiotensin II Type 1 receptor modulators from among the 265,242 molecules deposited in the NCI compound database (Release 4, 2012) by several rounds of In silico screening steps. Methods: The screening steps involved Lipinski's filter to eliminate the non-drug like candidates followed by fingerprint based similarity filtering using 950 known reference set of AT1 receptor binders. Further screening exercises such as, iterative GOLD based docking and binding free energy calculations were performed to arrive at potential AT1 receptor binding hit candidates. The 2D structural and bioactivity data of the known AT1 receptor modulators retrieved from BindingDB database were also critically reviewed. Results: Docking based virtual screening followed by high flexible docking resulted 10 best fit candidates, which had binding modes roughly similar to the cocrystallized ligand, ZD7155. Of the ten shortlisted candidates, NSC407757 had the binding affinity, on-par, as of the known reference ligand, ZD7155 towards AT1 receptor. An interesting observation of this study is that, the high binding affinity of the hit candidates may be attributed to the similar binding orientation and interactions as of the reference molecule independent of structural similarity with the known AT1 receptor modulators. Conclusion: The hit candidates reported in the present study hold promise as the potential new AT1 receptor modulators. Further study involving structural optimization, synthesis and In vitro binding experiments is warranted for the accelerated discovery of high efficacy novel AT1 receptor modulators.
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Mulatsari, Esti, Esti Mumpuni, and Ikhsan Ramadhan. "Skrining Virtual dan Elusidasi Moda Ikatan Senyawa dalam Bawang Putih (Allium Sativum L.) sebagai Penghambat Reseptor Advanced Glycation end Products." JURNAL ILMU KEFARMASIAN INDONESIA 17, no. 2 (October 29, 2019): 210. http://dx.doi.org/10.35814/jifi.v17i2.749.
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Diabetes memiliki dampak jangka panjang seperti aterosklerosis, nefropati, dan retinopati yang disebabkan oleh pembentukan Advanced Glycation End Products (AGEs). Penelitian secara in vitro pada ekstrak bawang putih (Allium sativum L.) terhadap aktivitas penghambatan pembentukan AGEs telah banyak dilakukan, namun belum diketahui mekanisme penghambatan dan senyawa apa yang berperan aktif dalam aktivitas penghambatan tersebut. Penelitian ini bertujuan untuk melakukan skrining virtual senyawa – senyawa dalam bawang putih (Allium sativum L.) yang aktif menghambat reseptor Advanced Glycation Endproduct sehingga senyawa aktif bisa dipertimbangkan sebagai kandidat senyawa obat. Metode yang digunakan adalah molecular docking dengan software PLANTS, YASARA, MarvinSketch, dan visualisasi ikatan senyawa uji pada asam amino reseptor menggunakan PyMOL, piridoksamin dan aminoguanidin digunakan sebagai kontrol positif inhibitor AGEs. Hasil docking 24 senyawa uji diperoleh tujuh senyawa yang aktif menghambat reseptor 3B75.pdb dan lima senyawa aktif menghambat reseptor 3O3U.pdb. Kandidat senyawa obat terdiri dari senyawa organosulfur, fenol dan flavonoid. Senyawa Ɣ-glutamil-sistein, E-ajoene, Nα-(1-Deoksi-Dfructosa-1-YL)-L-Arginin, Kaempferol-3-o-β-D-glukopiranosa, Iso-rhamnetin-3-o-β-D-glukopiranosa merupakan senyawa – senyawa dalam bawang putih yang memiliki kemampuan menghambat baik reseptor 3B75 maupun 3O3U dengan aktivitas yang lebih baik dari piridoksamin dan aminoguanidin.
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Palsaniya, Mahendiali, Bansari Patel, Nibedita Panigrahi, Daffodil Mohanta, Sonali Priyadarshini Parida, Dhruvin Kumar Patel, Mriganka Das, and Bidyut Kumar Kundu. "Effect of Positional Isomerism on Some Alcohol Based Drug towards Anti-Viral Activity against SARS-Cov-2: A Molecular Modeling Based Investigation." Journal of Biomedical Research & Environmental Sciences 2, no. 5 (May 2021): 383–91. http://dx.doi.org/10.37871/jbres1246.
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The severe acute respiratory syndrome coronavirus 2, better known as COVID-19, has become a major health concern worldwide. It has challenged the global healthcare sector like anything. It appeared in Wuhan, China, around November 2019, had spread to almost 187 countries due to its highly contagious nature. Quarantine, isolation, mask, and other precautionary measures remain the sole obliging strategy to decline the person-to-person transmissions. Amidst the pandemic, drug repurposing by identifying therapeutically potent molecule from the collection of pre-existing molecules by molecular docking and DFT methods are certainly fast and handy. Herein, this paper is dealing with 5 hydroxy based drugs such as 5-isopropyl-2-methylphenol (Carvacrol), 3-isopropyl-6-methylbenzene-1,2-diol, 2-isopropyl-5-methylbenzene-1,4-diol, 5-isopropyl-2-methylbenzene-1,3-diol, 2-isopropyl-5-methylbenzene-1,3-diol to discover the new possible COVID-19 inhibitors. The proteases PDB, e.g., 5r7y is used as hosts to calculate the interactions with hydroxy-based drugs as guests. Our research shows that 5-isopropyl-2-methylbenzene-1,3-diol is the most active, having binding energy –6.46 kcal/mol against 5r7y of SARS-CoV-2. Hence it is assumed that increasing number of alcohol group make the system more preferable towards SARS-CoV-2 protease protein 5r7y. It was also observed that relative binding energy among these alcohol-based drugs is further tuned by their positional isomerism property.
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Kells, NJ, NJ Beausoleil, MA Sutherland, and CB Johnson. "Post-natal development of EEG responses to noxious stimulation in pigs (Sus scrofa) aged 1–15 days." Animal Welfare 28, no. 3 (August 1, 2019): 317–29. http://dx.doi.org/10.7120/09627286.28.3.317.
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This study examined electroencephalographic (EEG) indices of acute nociception in pigs (Sus scrofa) aged 1, 5, 7, 10, 12 and 15 days, post-natal. Ten pigs per age were anaesthetised with halothane in oxygen and maintained at a light plane of anaesthesia. EEG was recorded bilaterally using a five-electrode montage. Following a 10-min baseline period, tails were docked using side-cutter pliers and recording continued for a further 5 min. Changes in the median frequency (F50), 95% spectral edge frequency (F95) and total power (PTOT) of the EEG were used to assess nociception. Tail-docking at one day of age induced no significant changes in the EEG spectrum. A typical nociceptive response, characterised by an increase in F50 and decrease in PTOT, was evident at ten days of age, with five and seven day old pigs exhibiting responses in either F50 or PTOT only. Pooling of data into ≤ 7 days of age and > 7 days of age revealed F50 was higher overall in the older group. Whilst PTOT decreased after docking in both groups, this response was larger and more prolonged in the older group. F95 increased after docking in the older pigs only. Overall, these data provide evidence of an increase in cortical responsiveness to noxious stimulation with increasing post-natal age, suggesting there may be qualitative differences in pain perception between age groups. Further, the data provide some support for current recommendations that tail-docking and other painful husbandry procedures be performed within seven days of birth in order to minimise their impact on animal welfare.
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Das, Sourav, Pooja Ghosh, Sudipta Koley, and Atanu Singha Roy. "Binding of naringin and naringenin with hen egg white lysozyme: A spectroscopic investigation and molecular docking study." Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 192 (March 2018): 211–21. http://dx.doi.org/10.1016/j.saa.2017.11.015.
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González-Durruthy, Michael, Riccardo Concu, Juan M. Ruso, and M. Natália D. S. Cordeiro. "New Mechanistic Insights on Carbon Nanotubes’ Nanotoxicity Using Isolated Submitochondrial Particles, Molecular Docking, and Nano-QSTR Approaches." Biology 10, no. 3 (February 25, 2021): 171. http://dx.doi.org/10.3390/biology10030171.
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Single-walled carbon nanotubes can induce mitochondrial F0F1-ATPase nanotoxicity through inhibition. To completely characterize the mechanistic effect triggering the toxicity, we have developed a new approach based on the combination of experimental and computational study, since the use of only one or few techniques may not fully describe the phenomena. To this end, the in vitro inhibition responses in submitochondrial particles (SMP) was combined with docking, elastic network models, fractal surface analysis, and Nano-QSTR models. In vitro studies suggest that inhibition responses in SMP of F0F1-ATPase enzyme were strongly dependent on the concentration assay (from 3 to 5 µg/mL) for both pristine and COOH single-walled carbon nanotubes types (SWCNT). Besides, both SWCNTs show an interaction inhibition pattern mimicking the oligomycin A (the specific mitochondria F0F1-ATPase inhibitor blocking the c-ring F0 subunit). Performed docking studies denote the best crystallography binding pose obtained for the docking complexes based on the free energy of binding (FEB) fit well with the in vitro evidence from the thermodynamics point of view, following an affinity order such as: FEB (oligomycin A/F0-ATPase complex) = −9.8 kcal/mol > FEB (SWCNT-COOH/F0-ATPase complex) = −6.8 kcal/mol ~ FEB (SWCNT-pristine complex) = −5.9 kcal/mol, with predominance of van der Waals hydrophobic nano-interactions with key F0-ATPase binding site residues (Phe 55 and Phe 64). Elastic network models and fractal surface analysis were performed to study conformational perturbations induced by SWCNT. Our results suggest that interaction may be triggering abnormal allosteric responses and signals propagation in the inter-residue network, which could affect the substrate recognition ligand geometrical specificity of the F0F1-ATPase enzyme in order (SWCNT-pristine > SWCNT-COOH). In addition, Nano-QSTR models have been developed to predict toxicity induced by both SWCNTs, using results of in vitro and docking studies. Results show that this method may be used for the fast prediction of the nanotoxicity induced by SWCNT, avoiding time- and money-consuming techniques. Overall, the obtained results may open new avenues toward to the better understanding and prediction of new nanotoxicity mechanisms, rational drug design-based nanotechnology, and potential biomedical application in precision nanomedicine.
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Nauli, Tigor. "PENENTUAN SISI AKTIF SELULASE ASPERGILLUS NIGER DENGAN DOCKING LIGAN." Jurnal Kimia Terapan Indonesia 16, no. 2 (December 10, 2014): 94–100. http://dx.doi.org/10.14203/jkti.v16i2.14.
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Letak dari sisi aktif selulase Aspergillus niger, yang akan menentukan aktivitas katalitiknya, dapat diketahui melalui komputasi. Sebuah ligan selobiosa dimodelkan untuk dapat melakukan simulasi docking pada molekul selulase yang telah diketahui struktur kristalnya. Melalui kalkulasi energi ikatan dan pendekatan optimasi memakai algoritma genetik Lamarckian, dapat dipilih konformasi molekul yang menunjukkan adanya daerah tertentu dengan energi terendah. Struktur yang memiliki daerah semacam ini dianggap mewakili konfigurasi terbaik terikatnya ligan pada sisi aktif yang dicari.Hasil perhitungan memperlihatkan bahwa tekukan protein yang membentuk celah konkaf diantara dua kelompok struktur b-sheet yang saling berlawanan arah pada molekul selulase merupakan sisi aktif dari enzim tersebut. Ligan dapat terikat disana melalui interaksi hidrofilik dengan residu asparagin (Asn20), serin (Ser111), dan glutamin (Gln158). Di salah satu ujung sisi aktif selulase terdapat residu aspartat (Asp99) dan glutamat (Glu116, Glu204) yang akan mempengaruhi aksi katalitik dari enzim selulase apabila residu-residu ini terikat oleh ion-ion divalen.Sisi aktif selulase ini merupakan gabungan dari domain pengikat substrat dan domain katalitik. Penambahan ion logam yang tepat pada sisi aktif enzim selulase Aspergillus niger dapat meningkatkan aktivitas spesifiknya.Kata kunci:docking, ligan, selulase, sisi ikatan, substrat The active site of cellulase from Aspergillus niger that affects the enzyme activity can be searched by computational methods. A ligand of cellobiose is modelled to perform docking simulation to cellulase with known crystal structure. By calculating the binding free energy and optimization approach using Lamarckian's genetic algorithm, a molecular conformation that has a region with the lowest energy value can be selected. The molecule structure with such region represents the best configuration of ligand bound to the active site.The calculation results that the concave cleft formed by protein folding of two anti-parallel b-sheet structures is the active site of the enzyme. A ligand would bind to the site through hydrophilic interactions with asparagine (Asn20), serine (Ser111), and glutamine (Gln158) residues. The aspartic acid (Asp99) and glutamic acid (Glu116, Glu204) residues that reside in one end of the active site determine the catalytic actions of the enzyme when they are binding with some metal ions.It is shown that the active site of this cellulase has substrate-binding domain and catalytic domain together. The introduction of specific metal ions to the active site of Asperillus niger cellulase will increase its specific activity.Keywords: binding site, cellulase, docking, ligand, substrate
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Ivanova, Larisa, Mati Karelson, and Dimitar A. Dobchev. "Multitarget Approach to Drug Candidates against Alzheimer’s Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets." Molecules 25, no. 8 (April 17, 2020): 1846. http://dx.doi.org/10.3390/molecules25081846.
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Alzheimer’s disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer’s disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets. These candidates were discovered by using state-of-the-art methods as molecular calculations (molecular docking and molecular dynamics), artificial neural networks and multilinear regression models. These methods were used for virtual screening of the publicly available library containing more than twenty thousand compounds. The experimental testing enabled us to confirm a multitarget drug candidate active at low micromolar concentrations against two targets, e.g., AChE and BACE1.
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Ayazoglu Demir, Elif, Ahmet Colak, Aylin Kalfa, Ahmet Yasar, Olcay Bekircan, and Melike Yildirim Akatin. "Investigation of tyrosinase inhibition by some 1,2,4 triazole derivative compounds: in vitro and in silico mechanisms." Turkish Journal of Biochemistry 44, no. 4 (December 4, 2018): 473–81. http://dx.doi.org/10.1515/tjb-2018-0273.
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Abstract Background Tyrosinase plays a central role in the biosynthesis pathway of melanin pigment. Melanin protects human skin against radiation and its unusual levels cause some skin disorders such as pregnancy scar, oldness spots and melanoma. Tyrosinase has also been linked to Parkinson’s and other neurodegenerative diseases. In addition, melanin plays a critical role as a defense molecule for insects during wound healing and is important for their life. Therefore, determination of inhibitor molecules for tyrosinase has a promising potential for therapies of some diseases and is an alternative method for keeping insects under control. Material and methods In this study, 1-hepthyl-3-(4-methoxybenzyl)-4H-1,2,4-triazole-5-one derivative (A6, A8, A15) and 3-(4-chlorophenyl)- 5-(4-methoxybenzyl)-4H-1,2,4-triazole (B5, B9, B13) derivative compounds were evaluated in terms of their potential for mushroom tyrosinase inhibition. IC50 values of these six molecules were determined. Results It was seen that B9 molecule was the most effective inhibitor. Docking studies also nearly supported this end result. Tyrosinase inhibition type and Ki value were found to be uncompetitive and 370.7±0.3 μM, respectively, in the presence of B9 compound. Conclusion These results suggest that B9 compound is a potential tyrosinase inhibitor.
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Elhassan, Fatima Khalid, Yassir A. Almofti, Khoubieb Ali Abd-elrahman, Mashair AA Nouri, and Elsideeq EM Eltilib. "Structural Analysis of Avian Encephalomyelitis Virus Polyprotein for Development of Multi Epitopes Vaccine Using Immunoinformatics Approach." Journal of Pure and Applied Microbiology 15, no. 1 (February 13, 2021): 262–78. http://dx.doi.org/10.22207/jpam.15.1.20.
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Avian Encephalomyelitis (AE) is the disease caused by avian encephalomyelitis virus (AEV). The disease mainly affects young birds nervous system worldwide causing high morbidity and variable mortality rate in chicks and noticed egg dropping and hatchability in mature hens. Vaccination is the only way to control AEV infection since there is no treatment yet to the avian encephalomyelitis. This study aimed to use immunoinformatics approaches to predict multi epitopes vaccine from the AEV polyprotein that could elicit both B and T cells. The vaccine construct comprises 482 amino acids obtained from epitopes predicted against B and T cells by IEDB server, adjuvant, linkers and 6-His-tag. The chimeric vaccine was potentially antigenic and nonallergic and demonstrated thermostability and hydrophilicity in protparam server. The solubility of the vaccine was measured in comparison to E. coli proteins. The stability was also assessed by disulfide bonds engineering to reduce the high mobility regions in the designed vaccine. Furthermore molecular dynamics simulation further strengthen stability of the predicted vaccine. Tertiary structure of the vaccine construct after prediction, refinement was used for molecular docking with chicken alleles BF2*2101 and BF2*0401 and the docking process demonstrated favourable binding energy score of -337.47 kcal/mol and -326.87 kcal/mol, respectively. Molecular cloning demonstrated the potential clonability of the chimeric vaccine in pET28a(+) vector. This could guarantee the efficient translation and expression of the vaccine within suitable expression vector.
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Syafitri, Riyanti Weni, Azzania Fibriani, and Reza Aditama. "Selection of Indonesian Medicinal Plant Active Compounds as Inhibitor Candidates of Oncoproteins E6 and E7 Human Papillomavirus Type 16 by Molecular Docking." 3BIO: Journal of Biological Science, Technology and Management 3, no. 1 (July 13, 2021): 9–17. http://dx.doi.org/10.5614/3bio.2021.3.1.2.
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Cervical cancer cases caused by infection with Human Papillomavirus (HPV), especially HPV 16 (60.5% of cases) continue to increase every year with a high mortality rate. The current anti-cancer drugs were not only specifically targeting cancer cells, but healthy cells and can cause serious side effects. Therefore, it is necessary to find safer alternative therapies, e.g., using active compounds from natural products. The purpose of this study was to find the active compounds of Indonesian medicinal plants potentially as an inhibitor of oncoprotein E6 and E7 HPV 16, the main protein causing cervical cancer by in silico method. In this study, 711 active compounds from 187 medicinal plant species were selected based on molecular weight, solubility, gastrointestinal absorption index, and drug-likeness. Compounds that meet the criteria were tested for their affinity and interaction profile with E6 and E7 proteins through the molecular docking method. The results of this study showed 164 compounds that met the criteria. The molecular docking analysis showed nine of the most potent compounds as E6 inhibitors on the E6AP binding site and six compounds on the p53 binding site. Besides that, there were eleven most potent compounds as E7 inhibitors. The results of this study indicate that there are natural compounds that can inhibit E6 and E7 proteins and have further potential to be used as anti-HPV drugs. However, further research is needed to test these compounds in vitro and in vivo.
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Usha, Talambedu, Pranav Tripathi, Veena Pande, and Sushil Kumar Middha. "Molecular Docking and Quantum Mechanical Studies on Pelargonidin-3-Glucoside as Renoprotective ACE Inhibitor." ISRN Computational Biology 2013 (March 28, 2013): 1–4. http://dx.doi.org/10.1155/2013/428378.
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Background and Aim. Despite tangible progress in recent years, substantial therapeutic challenges remain unexplored in nephropathy, particularly in diabetic patient. Addressing these challenges requires identification of novel drugs and development of noninvasive and cost-effective methods to select the most appropriate therapeutic option for the disease. Angiopathic nephropathy is one of the complications of diabetes mellitus and is becoming the single most important reason for end-stage renal disease in the western world. This study has investigated the inhibitory effect of a library naturally occurring nonprotein compounds that inhibit angiotensin converting enzyme (ACE). Materials and Methods. Docking studies of ACE protein with natural compounds and synthetic commercial drug perindopril were done using AutoDock, FlexX, and Hex. Toxicity predictions were carried out using OpenTox. Quantum mechanical properties were studied using GAMESS. Results. Pelargonidin-3-glucoside could be used as a potent renoprotective drug candidate, which inhibits ACEII. It has low toxicity and its quantum mechanical properties are comparable to those of commercial drugs.
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Shunmugaperumal, Selvaraj, Saranya Dhasarathan, Kamatchi P. Selvaraj, Ilango Kaliappan, and Bathula Siva Kumar. "Spectral and Electrochemical Sensing Studies of Unsymmetrical Schiff Bases having Enhanced Antifungal Activity." Asian Journal of Chemistry 33, no. 10 (2021): 2400–2410. http://dx.doi.org/10.14233/ajchem.2021.23351.
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Novel unsymmetrical Schiff bases comprising azomethine spin-off having ferrocene moiety at one end and simple aromatic component attached imine at other end, capable of sensing multiple metal ions have been synthesized. The MLCT charge transfer band in UV-Visible studies upon coordination with metal ions with receptors is recorded particularly for Cu2+ ions. The observed ΔEp values with change in scan rate for metal free and metal added receptor solution suggest quasi-reversible process. Agar well diffusion method and molecular docking studies reveals that the synthesized compounds inhibit more efficiently fungi rather than bacteria, which hampers the progress of microbial research, as the available antifungal agents are minimal compared to antibacterial counterpart.
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Türkeş, Cüneyt. "Investigation of Potential Paraoxonase-I Inhibitors by Kinetic and Molecular Docking Studies: Chemotherapeutic Drugs." Protein & Peptide Letters 26, no. 6 (July 4, 2019): 392–402. http://dx.doi.org/10.2174/0929866526666190226162225.
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Background: Metabolic processes in living organisms are closely related to the catalytic activity of enzymes. Changes in enzyme activity cause various diseases e.g., neurological, cancer, metabolic and cardiovascular. Most of the current therapeutic drugs available in clinical utilization function as enzyme inhibitors. Objective: The main goal of the current study to contribute to this growing drug design area (such as medication discovery and development) by investigating protein-drug interactions. Methods: The paraoxonase-I (PON1) enzyme was purified from human serum by using different and simple chromatographic techniques. Additionally, it was investigated inhibition effects of some chemotherapeutic drugs on the PON1. Results: The purification results for PON1 depicted a 3880.83 EU/mg proteins specific activity and the molecular weight was calculated as 43 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These drugs found to strongly inhibit PON1, with IC50 values ranging from 0.222±0.002 to 688.300±0.897 µM. Ki constants for vincristine sulfate, epirubicin hydrochloride, and doxorubicin hydrochloride were determined to be 0.235±0.032 µM, 221.400±29.270 µM, and 913.300±201.000 µM, respectively. Conclusion: These drugs showed in competitive inhibition. Also, the molecular docking poses of these agents inside the catalytic sites of 1V04 and 3SRE were analysis.
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Wu, Mingquan, Hong-Ling Du, Xu Zhou, Wei Peng, Limei Liu, Zhong Zhang, and He Tu. "Network Pharmacology-Based Analysis of the Underlying Mechanism of Huajiao for Pain Relief." Evidence-Based Complementary and Alternative Medicine 2021 (April 4, 2021): 1–11. http://dx.doi.org/10.1155/2021/5526132.
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Objective. Pain is a common symptom among patients, and pain management is an important clinical practice topic. The mechanism of Huajiao (HJ; Zanthoxylum bungeanum Maxim.) and its effective components for treating pain was explored using network pharmacology and molecular docking to verify its pain relief function in traditional medical practice. Methods. HJ’s components were collected via the Traditional Chinese Medicine Systems Pharmacology platform and published studies. HJ-associated target proteins were predicted using the drug similarity rule via Swiss Target Prediction. Online Mendelian Inheritance in Man was used to search for pain-related genes and proteins, and the Database of Interacting Proteins was used to obtain the human interactive target proteins. The compound-target-disease network of HJ for pain relief was constructed with protein-protein interaction networks. The obtained target proteins were uploaded on the Database for Annotation, Visualization, and Integrated Discovery to annotate, visualize, and integrally discover the related signaling pathway, and semiflexible molecular docking by Autodock Vina was applied to verify the potential mechanism. Results. A total of 157 molecules in HJ were obtained, and the top 20 active components or active groups were mainly focused on the amide alkaloids (e.g., [6RS]-[2E,7E,9E]-6-hydroxy-N-[2-hydroxy-2-methylpropyl]-11-oxo-2,7,9-dodecatrienamide and [2E,7E,9E]-N-[2-hydroxy-2-methylpropyl]-11-ethoxy-6-hydroxy-dodeca-2,7,9-trienamide). Also, the 66 main targets were filtered from 746 predicted targets and 928 pain-related targets through module Network Analyzer in Cytoscape 3.6.0. Finally, there were 3 critical signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin, and IκB kinase-nuclear factor κB-cyclooxygenase 2 based on integrated discovery with 54 enriched signaling pathways. Conclusions. HJ is used as a pain relief and has multicomponents, multitargets, and multiapproaches. Amide alkaloids are important substance bases, and HJ is more suitable for treating inflammatory pain.
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Prieto-Martínez, Fernando, and José Medina-Franco. "Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics." Biomolecules 8, no. 3 (July 23, 2018): 61. http://dx.doi.org/10.3390/biom8030061.
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Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.