To see the other types of publications on this topic, follow the link: Ligand Structure Effects.
Journal articles on the topic 'Ligand Structure Effects'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Ligand Structure Effects.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Zhao, Yi, Qun Chen, Mingyang He, et al. "Tris(Butadiene) Compounds versus Butadiene Oligomerization in Second-Row Transition Metal Chemistry: Effects of Increased Ligand Fields." Molecules 26, no. 8 (2021): 2220. http://dx.doi.org/10.3390/molecules26082220.
Full textAbstract:
The geometries, energetics, and preferred spin states of the second-row transition metal tris(butadiene) complexes (C4H6)3M (M = Zr–Pd) and their isomers, including the experimentally known very stable molybdenum derivative (C4H6)3Mo, have been examined by density functional theory. Such low-energy structures are found to have low-spin singlet and doublet spin states in contrast to the corresponding derivatives of the first-row transition metals. The three butadiene ligands in the lowest-energy (C4H6)3M structures of the late second-row transition metals couple to form a C12H18 ligand that binds to the central metal atom as a hexahapto ligand for M = Pd but as an octahapto ligand for M = Rh and Ru. However, the lowest-energy (C4H6)3M structures of the early transition metals have three separate tetrahapto butadiene ligands for M = Zr, Nb, and Mo or two tetrahapto butadiene ligands and one dihapto butadiene ligand for M = Tc. The low energy of the experimentally known singlet (C4H6)3Mo structure contrasts with the very high energy of its experimentally unknown singlet chromium (C4H6)3Cr analog relative to quintet (C12H18)Cr isomers with an open-chain C12H18 ligand.
2
Genest, Alexander, Sven Krüger, Alexei B. Gordienko, and Notker Rösch. "Gold-Thiolate Clusters: A Relativistic Density Functional Study of the Model Species Au13(SR)n, R = H, CH3, n = 4, 6, 8." Zeitschrift für Naturforschung B 59, no. 11-12 (2004): 1585–99. http://dx.doi.org/10.1515/znb-2004-11-1232.
Full textAbstract:
The binding of sulfanyl and alkylsulfanyl model ligands to gold clusters was studied for the case of Au13(SR)n with R = H, CH3 and n = 4, 6, 8. Accurate all-electron electronic structure calculations and geometry optimizations of these gold-thiolate clusters have been performed with a scalar relativistic Kohn-Sham procedure as implemented in the density functional program PARAGAUSS. In all structures obtained, bridge coordination was preferred for both types of ligands; no higher coordinated sites where occupied. While in many cases ligand decoration did not change the overall structure of the Au13 core, also more open structures with Au-Au distances elongated beyond the bulk value have been obtained. The effects due to increasing ligand decoration were small: a small decrease of the binding energy per ligand does not exclude higher ligand coverages. The differences between the model ligands SH and SCH3 were consistent in all cases considered: SCH3 exhibits weaker binding and a slightly smaller charge separation between cluster core and ligand shell, which amounts up to about 1.5 e for 8 ligands. Overall, the Au13 core of the clusters was found to be quite flexible. This can be rationalized by the fact that the calculated binding energy per ligand is comparable or even exceeds the binding energy per atom in Au13.
3
Bilodeau, Camille, Edmond Y. Lau, Steve Cramer, and Shekhar Garde. "The Effects of Ligand Structure on Protein-Multimodal Ligand Interactions." Biophysical Journal 116, no. 3 (2019): 477a. http://dx.doi.org/10.1016/j.bpj.2018.11.2579.
Full text
4
HARRIS, DANNI L., and GILDA H. LOEW. "Proximal ligand effects on electronic structure and spectra of compound I of peroxidases." Journal of Porphyrins and Phthalocyanines 05, no. 03 (2001): 334–44. http://dx.doi.org/10.1002/jpp.316.
Full textAbstract:
Computational studies exploring the extent to which differences in proximal axial ligands modulate structure, spectra, and function of peroxidases have been performed. To this end, three heme models of compound I were characterized differing only in the axial ligand. The axial ligands considered were L = ImH , Im -, that are alternative protonation models for a typical peroxidase with an imidazole ligand such as horseradish peroxidase (HRP-I), and L = SCH - that is a model for an unsual peroxidase, chloroperoxidase (CPO-I). Density functional calculations (DFTs) were performed to determine the optimized geometries and electronic structure of each of these three species. Their electronic spectra were also calculated at the DFT optimized geometries, using the INDO/S/CI method. The results of these studies led to the following conclusions: (1) the presence of the nearby Asp in a typical peroxidase does indeed decrease the energy required to deprotonate the imidazole making the two forms essentially degenerate, (2) neither the state of protonation of the imidazole ligand nor the change in axial ligand from an imidazole in typical peroxidases such as HRP to a mercaptide in CPO significantly alters the characteristics of the lowest energy spin state or the electronic structure of compound I in a way that can obviously affect function, (3) both the Im - and ImH forms of the peroxidase compound I (HRP-I) lead to the same dramatic reduction in intensity relative to the ferric resting form observed experimentally. However, only in the ImH form of HRP-I does the calculated relative shift of one component of the Soret bands relative to CPO-I agree with that observed in the transient spectra of HRP-I compared to CPO-I. These results taken together strongly indicate that factors other than the nature of the proximal axial ligand are the main determinants of function.
5
Langelaan, David N., and Jan K. Rainey. "Membrane catalysis of peptide–receptor bindingThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 88, no. 2 (2010): 203–10. http://dx.doi.org/10.1139/o09-129.
Full textAbstract:
The membrane catalysis hypothesis states that a peptide ligand activates its target receptor after an initial interaction with the surrounding membrane. Upon membrane binding and interaction, the ligand is structured such that receptor binding and activation is encouraged. As evidence for this hypothesis, there are numerous studies concerning the conformation that peptides adopt in membrane mimetic environments. This mini-review analyzes the features of ligand peptides with an available high-resolution membrane-induced structure and a characterized membrane-binding region. At the peptide–membrane interface, both amphipathic helices and turn structures are commonly formed in peptide ligands and both hydrophobic and electrostatic interactions can be responsible for membrane binding. Apelin is the ligand to the G-protein coupled receptor (GPCR) named APJ, with various important physiological effects, which we have recently characterized both in solution and bound to anionic micelles. The structural changes that apelin undergoes when binding to micelles provide strong evidence for membrane catalysis of apelin–APJ interactions.
6
O'Callaghan, Chris A., Aleksandra A. Watson, Angharad E. Fenton-May, and Charita M. Christou. "Structure and function of the activating receptor CLEC-2. (134.10)." Journal of Immunology 182, no. 1_Supplement (2009): 134.10. http://dx.doi.org/10.4049/jimmunol.182.supp.134.10.
Full textAbstract:
Abstract We are studying the immune recognition of diseased or damaged cells. In cytotoxic cells, the C-type lectin-like receptor NKG2D plays a key role in this distinction. A number of related receptors are expressed on immune cells and we are studying their function. CLEC-2 is an activating receptor which is also expressed on platelets. We have crystallized CLEC-2 and solved its structure. We have used recombinant CLEC-2 as a probe to identify an endogenous ligand for CLEC-2, which is known as podoplanin. The podoplanin-CLEC-2 interaction triggers an activating signal in the cell expressing CLEC-2. We have also solved the crystal structure of rhodocytin, an exogenous ligand for CLEC-2. The structures of both ligand and receptor allow us to produce molecular models of the interactions and its effects. These suggest that the ligand-receptor interactions will cluster CLEC-2 on the cell surface. We have used surface plasmon resonance to define the binding characteristics of the interactions of CLEC-2 with both its exogenous and endogenous ligands.
7
Halbert, Stéphanie, and Hélène Gérard. "A computational study of the effects of ancillary ligands on copper(i)–ethylene interaction." New Journal of Chemistry 39, no. 7 (2015): 5410–19. http://dx.doi.org/10.1039/c5nj00546a.
Full text
8
Pippal, Jyotsna B., and Peter J. Fuller. "Structure–function relationships in the mineralocorticoid receptor." Journal of Molecular Endocrinology 41, no. 6 (2008): 405–13. http://dx.doi.org/10.1677/jme-08-0093.
Full textAbstract:
The signature action of aldosterone in the regulation of electrolyte and fluid balance is well established. However, the role of aldosterone as an important contributor to morbidity and mortality in heart failure has gained a heightened interest in recent years, but the mechanisms of this action are not well understood. Aldosterone is the principal physiological ligand for the mineralocorticoid receptor (MR), a ligand-activated transcription factor, that also binds to the physiological glucocorticoid, cortisol. Both classes of hormones bind with similar affinity to the MR, but the molecular basis of selective and tissue-specific effects of MR ligands is not yet fully documented. The structural and functional determinants of MR function are described and their significance is discussed.
9
Zhu, Yu, Qiaohong Li, Dongsheng Li, Jian Zhang, and Lei Zhang. "Functional ligand directed assembly and electronic structure of Sn18-oxo wheel nanoclusters." Chemical Communications 57, no. 42 (2021): 5159–62. http://dx.doi.org/10.1039/d1cc00651g.
Full textAbstract:
The bilayer hexagonal Sn<sub>18</sub>-oxo cluster, as the largest tin-oxo wheel, was constructed by a ligand templating method. Moreover, the ligands also show important effects on electronic structure and third-order nonlinear optical property of the wheel.
10
Chiu, Cheng-Chang, Gene-Hsiang Lee, Tien-Sung Lin, and Shie-Ming Peng. "Ligand effects on the structure, mixed-valence sites and magnetic properties of novel pentanickel string complexes." Dalton Transactions 48, no. 23 (2019): 8464–77. http://dx.doi.org/10.1039/c9dt01363f.
Full textAbstract:
Four redox pairs of pentanickel metal string complexes containing pyridine-, naphthyridine- and the corresponding sulfonyl substituted ligands were synthesized to examine the ligand effects on their electronic structures and magnetic properties.
11
Zlatovic, Mario, Vladimir Sukalovic, Sladjana Kostic-Rajacic, Deana Andric, and Goran Roglic. "Influence of N-1 substituent properties on binding affinities of arylpiperazines to the binding site of 5-HT1A receptor." Journal of the Serbian Chemical Society 71, no. 11 (2006): 1125–35. http://dx.doi.org/10.2298/jsc0611125z.
Full textAbstract:
Serotonin receptors (5-HTRs), especially the 5-HT1A subtype, have been the subject of intensive research for the past decade, due to their function in human physiology. Several structurally different classes of ligands are known to bind to the 5-HT1A receptor, but arylpiperazine derivatives are among the most important ligands. In the work, docking analyses were used to explain the binding affinities of a series of ligands with different N-1 substituent. All ligands had in common the arylpiperazine structure, while the N-1 subsistent was modified to investigate the influence of ligand structure on its binding affinity. The shape and size, as well as the rigidity of the subsistents were altered to investigate the possible effects on the formation of the receptor - ligand complex.
12
Tziridis, Anastasia, Daniel Rauh, Piotr Neumann, et al. "Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues." Biological Chemistry 395, no. 7-8 (2014): 891–903. http://dx.doi.org/10.1515/hsz-2014-0158.
Full textAbstract:
Abstract A high-resolution crystallographic structure determination of a protein–ligand complex is generally accepted as the ‘gold standard’ for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein–ligand interactions and emphasize the difficulties in predicting affinity from structure.
13
Nin-Hill, Alba, Nicolas Pierre Friedrich Mueller, Carla Molteni, Carme Rovira, and Mercedes Alfonso-Prieto. "Photopharmacology of Ion Channels through the Light of the Computational Microscope." International Journal of Molecular Sciences 22, no. 21 (2021): 12072. http://dx.doi.org/10.3390/ijms222112072.
Full textAbstract:
The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.
14
Shang, Jinsai, Richard Brust, Patrick R. Griffin, Theodore M. Kamenecka, and Douglas J. Kojetin. "Quantitative structural assessment of graded receptor agonism." Proceedings of the National Academy of Sciences 116, no. 44 (2019): 22179–88. http://dx.doi.org/10.1073/pnas.1909016116.
Full textAbstract:
Ligand–receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure–function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity–conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.
15
Kuznetsov, Aleksei, and Jaak Järv. "Ligand structure controlled allostery in cAMP-dependent protein kinase catalytic subunit." Open Life Sciences 4, no. 2 (2009): 131–41. http://dx.doi.org/10.2478/s11535-009-0012-6.
Full textAbstract:
AbstractProtein kinase A (cAMP dependent protein kinase catalytic subunit, EC 2.7.11.11) binds simultaneously ATP and a phosphorylatable peptide. These structurally dissimilar allosteric ligands influence the binding effectiveness of each other. The same situation is observed with substrate congeners, which reversibly inhibit the enzyme. In this review these allosteric effects are quantified using the interaction factor, which compares binding effectiveness of ligands with the free enzyme and the pre-loaded enzyme complex containing another ligand. This analysis revealed that the allosteric effect depends upon structure of the interacting ligands, and the principle “better binding: stronger allostery” observed can be formalized in terms of linear free-energy relationships, which point to similar mechanism of the allosteric interaction between the enzyme-bound substrates and/or inhibitor molecules. On the other hand, the type of effect is governed by ligand binding effectiveness and can be inverted from positive allostery to negative allostery if we move from effectively binding ligands to badly binding compounds. Thus the outcome of the allostery in this monomeric enzyme is the same as defined by classical theories for multimeric enzymes: making the enzyme response more efficient if appropriate ligands bind.
16
May, Nóra Veronika, Kevin Nys, H. Y. Vincent Ching та ін. "Crystal structures of zinc(II) complexes with β-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering". Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 77, № 2 (2021): 193–204. http://dx.doi.org/10.1107/s2052520621000299.
Full textAbstract:
The coordination properties of four hydroxypyridinecarboxylates, designed for the treatment of iron-overloading conditions as bidentate O,O′-donor ligands, have been studied with ZnII in the solid state. The coordination compounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-carboxylate (A1, C7H6NO3), 1,6-dimethyl-4-oxidopyridinium-3-carboxylate (A2, C8H8NO3), 1,5-dimethyl-4-oxido-pyridinium-3-carboxylate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxylate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyridine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron complement the bis-ligand complex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal complexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII complexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridinolate O atom of the neighbouring complex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1–3 are similar, having alternating hydrophilic and hydrophobic layers, however the similarity is broken in 4. The obtained coordination geometries are compared with their previously determined CuII analogues. The study of the individual complexes is complemented with a comprehensive analysis of ZnII complexes with oxygen donor ligands with data from the Cambridge Structural Database.
17
Murphy, Patrick B., Feng Liu, Stephen C. Cook, et al. "Structural control of Au and Au–Pd nanoparticles by selecting capping ligands with varied electronic and steric effects." Canadian Journal of Chemistry 87, no. 11 (2009): 1641–49. http://dx.doi.org/10.1139/v09-127.
Full textAbstract:
Weakly interacting ligands including three Gemini surfactants, didodecyldimethylammonium bromide (DDAB), and amines (RNH2, R2NH, and R3N) were used to prepare Au nanoparticles (NPs). Aqueous Au NPs capped with DDAB and Gemini surfactants showed similar sizes (3–4 nm), whereas toluene-based NPs stabilized with DDAB, amines, and their mixtures range from 2.5 to 9.3 nm. Ligand effect on Au–Pd NP structure was also studied with EXAFS. These findings were consistently accounted for by considering the ligand’s electronic/steric effects and mixed ligands coadsorption, and suggest useful ways to control NP structure by manipulating the two effects and using mixed capping ligands.
18
Shimbayashi, Takuya, and Ken-ichi Fujita. "Recent Advances in Homogeneous Catalysis via Metal–Ligand Cooperation Involving Aromatization and Dearomatization." Catalysts 10, no. 6 (2020): 635. http://dx.doi.org/10.3390/catal10060635.
Full textAbstract:
Recently, an increasing number of metal complex catalysts have been developed to achieve the activation or transformation of substrates based on cooperation between the metal atom and its ligands. In such “cooperative catalysis,” the ligand not only is bound to the metal, where it exerts steric and electronic effects, but also functionally varies its structure during the elementary processes of the catalytic reaction. In this review article, we focus on metal–ligand cooperation involving aromatization and dearomatization of the ligand, thus introducing the newest developments and examples of homogeneous catalytic reactions.
19
Balius, Trent E., Marcus Fischer, Reed M. Stein, et al. "Testing inhomogeneous solvation theory in structure-based ligand discovery." Proceedings of the National Academy of Sciences 114, no. 33 (2017): E6839—E6846. http://dx.doi.org/10.1073/pnas.1703287114.
Full textAbstract:
Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST’s impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.
20
Kühl, Olaf. "The natural bite angle — Seen from a ligand's point of view." Canadian Journal of Chemistry 85, no. 3 (2007): 230–38. http://dx.doi.org/10.1139/v07-023.
Full textAbstract:
The natural bite angle concept is examined using N,N′-bisphosphino urea ligands as rigid scaffolds. The ligand has an upper limit of about 95° for the observed bite angle in chelate complexes, but prefers a much lower one. The ligand can be described as possessing downward flexibility. The dependence of the bite angle on the P—P distance within the ligand and the M—P bond length is illustrated. The metal tries to force the ligand into its own preferred structure, whereas the ligand wants to achieve a short P—P distance. A truly rigid ligand such as the N,N′-bisphosphino urea family is thus seen to clearly discriminate between metal atoms according to their individual assertiveness, using the P—P distance in the complex as a measure. Although the natural bite angle concept is valid and helpful in determining the possible bite-angle range for ligands before it is actually synthesised, its practical applicability seems to be limited to those cases where the flexibility range of the ligand allows for only one metal-preferred bite angle to be realized.Key words: natural bite angle, ligand effects, ligand design.
21
Luttrell, Louis M. "Minireview: More Than Just a Hammer: Ligand “Bias” and Pharmaceutical Discovery." Molecular Endocrinology 28, no. 3 (2014): 281–94. http://dx.doi.org/10.1210/me.2013-1314.
Full textAbstract:
Abstract Conventional orthosteric drug development programs targeting G protein-coupled receptors (GPCRs) have focused on the concepts of agonism and antagonism, in which receptor structure determines the nature of the downstream signal and ligand efficacy determines its intensity. Over the past decade, the emerging paradigms of “pluridimensional efficacy” and “functional selectivity” have revealed that GPCR signaling is not monolithic, and that ligand structure can “bias” signal output by stabilizing active receptor states in different proportions than the native ligand. Biased ligands are novel pharmacologic entities that possess the unique ability to qualitatively change GPCR signaling, in effect creating “new receptors” with distinct efficacy profiles driven by ligand structure. The promise of biased agonism lies in this ability to engender “mixed” effects not attainable using conventional agonists or antagonists, promoting therapeutically beneficial signals while antagonizing deleterious ones. Indeed, arrestin pathway-selective agonists for the type 1 parathyroid hormone and angiotensin AT1 receptors, and G protein pathway-selective agonists for the GPR109A nicotinic acid and μ-opioid receptors, have demonstrated unique, and potentially therapeutic, efficacy in cell-based assays and preclinical animal models. Conversely, activating GPCRs in “unnatural” ways may lead to downstream biological consequences that cannot be predicted from prior knowledge of the actions of the native ligand, especially in the case of ligands that selectively activate as-yet poorly characterized G protein-independent signaling networks mediated via arrestins. Although much needs to be done to realize the clinical potential of functional selectivity, biased GPCR ligands nonetheless appear to be important new additions to the pharmacologic toolbox.
22
Ashok, Kumar T., and B. Rajagopal. "PDTDB – An Integrative Structural Database and Prediction Server for Plant Metabolites and Therapeutic Drug Targets." International Journal of Current Research 9, no. 2 (2017): 46537–41. https://doi.org/10.5281/zenodo.562286.
Full textAbstract:
Understanding the biological phenomena of sequence, structure, function, metabolism, and molecular interactions of species is crucial to identify or analyze the biological problems in the ideal way. Integration of all data facilitates unified access to the key problem. PDTDB (Phytochemical and Drug Target DataBase) is an integrative structural database, which contains information about the plants (secondary metabolites, plant anatomy, side effects and medicinal properties), ligands (3D molecular structure, SMILES string, side effects and medicinal properties), therapeutic drug targets (3D molecular structure, sequence, mechanism of the drug target, disease nature and disease symptoms), molecular dockings (target-ligand complex interaction, drug action, home remedies and docking results), and structure activity relationship between diseases, therapeutic targets, plants and phytochemicals. The database provides keyword or accession number search, similar phytochemical structures search using SMILES string or by sketching the structure in the chemical structure editor, phytochemical structures with similar molecular formula search, binding structure search, and browse and/or search database entries from the sortable table. It supports predicting physicochemical properties of sequence and structures, and interactive visualization of structures in various models. PDTDB is freely accessible at https://pdt.biogem.org.
23
Jiang, Ning, Wei Chen, Prithiviraj Jothikumar та ін. "Effects of anchor structure and glycosylation of Fcγ receptor III on ligand binding affinity". Molecular Biology of the Cell 27, № 22 (2016): 3449–58. http://dx.doi.org/10.1091/mbc.e16-06-0470.
Full textAbstract:
Isoforms of the Fcγ receptor III (FcγRIII or CD16) are cell surface receptors for the Fc portion of IgG and important regulators of humoral immune responses. Different ligand binding kinetics of FcγRIII isoforms are obtained in three dimensions by surface plasmon resonance and in two dimensions by a micropipette adhesion frequency assay. We show that the anchor structure of CD16 isoforms isolated from the cell membrane affects their binding affinities in a ligand-specific manner. Changing the receptor anchor structure from full to partial to none decreases the ligand binding affinity for human IgG1 (hIgG1) but increases it for murine IgG2a (mIgG2a). Removing N-glycosylation from the CD16 protein core by tunicamycin also increases the ligand binding affinity. Molecular dynamics simulations indicate that deglycosylation at Asn-163 of CD16 removes the steric hindrance for the CD16-hIgG1 Fc binding and thus increases the binding affinity. These results highlight an unexpected sensitivity of ligand binding to the receptor anchor structure and glycosylation and suggest their respective roles in controlling allosterically the conformation of the ligand binding pocket of CD16.
24
Калиновская, И. В. "Люминесцентные свойства соединений европия(III) с хинолиновой кислотой и фосфорсодержащими нейтральными лигандами". Журнал технической физики 127, № 8 (2019): 231. http://dx.doi.org/10.21883/os.2019.08.48034.332-18.
Full textAbstract:
AbstractLuminescent mixed-ligand europium(III) complexes with quinolinic acid and phosphorus-containing neutral ligands with a dimeric structure of the composition Eu_2(QA)_3 · 3Н_2О, Eu_2(QA)_3 · D · 2Н_2О, where QA is quinolinic acid and D is hmpa (hexamethylphosphortriamide), tppo (triphenylphosphinoxide), (hmpa), or Et_6pa (hexaethylphosphortriamide), are synthesized. The thermal and spectral-luminescent properties of the synthesized complex mixed-ligand europium(III) compounds are studied. It is shown that the detachment of water and neutral ligand molecules during thermolysis occurs in two stages with endothermic effects and that the complex compounds are stable at temperatures up to 320°С. It is found by IR spectroscopy that quinolinic acid coordinates to the europium(III) ion by two carboxylate ions. The low luminescence intensity of mixed-ligand europium(III) quinolinates is explained by inefficient electronic excitation energy transfer from quinolinic acid and phosphorus-containing neutral ligands to europium ions.
25
Shin, Kyungsoo, Calem Kenward, and Jan K. Rainey. "Apelinergic System Structure and Function." Comprehensive Physiology 8, no. 1 (2018): 407–50. https://doi.org/10.1002/j.2040-4603.2018.tb00012.x.
Full textAbstract:
ABSTRACTApelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G‐protein‐coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand‐AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C‐terminal to dibasic proprotein convertase cleavage sites. The C‐terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform‐dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure‐function correlation, with a particular focus on isoform‐dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform‐dependent pharmacological properties, and biological membrane‐mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407‐450, 2018.
26
TANG, LIDA, JIANGWU WANG, WEIREN XU, and CHENG-LUNG CHEN. "SIMULATION STUDY OF THE EFFECTS OF LIGAND ON THE ACTIVE ZONE OF THE PEPTIDE DEFORMYLASE." Journal of Theoretical and Computational Chemistry 05, no. 01 (2006): 99–110. http://dx.doi.org/10.1142/s021963360600209x.
Full textAbstract:
Molecular Dynamics (MD) simulation was carried out to study the conformation changes of the active zone of a Peptide Deformylase. Both the simulation with and without ligand were initialed from the crystal structure (1bs8). The tripeptide, Met-Ala-Ser (MAS), was used as the ligand in simulation. After thermal equilibrium, trajectories of one nanosecond MD run was collected and analyzed. The simulation result was compared with the NMR and crystal observed structures. The simulation shows that within one nanosecond time domain, only local deformation of protein occurred. The active zone was defined by the associated active atomic sites and torsion angles. It is indicated that the active zone from the simulation without ligand is similar to that determined from NMR experiment in solution. The active zone is altered at some residues by comparison with the data from the simulation with or without ligand, which is different from the results obtained from crystal structures. It is suggested that the active zone of PDF in solution could be influenced by the ligand locally.
27
Denzinger, Katrin, Trung Ngoc Nguyen, Theresa Noonan, Gerhard Wolber, and Marcel Bermudez. "Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors." International Journal of Molecular Sciences 21, no. 24 (2020): 9728. http://dx.doi.org/10.3390/ijms21249728.
Full textAbstract:
G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.
28
Khajavian, Ruhollah, Vida Jodaian, Fatemeh Taghipour, Joel T. Mague, and Masoud Mirzaei. "Roles of Organic Fragments in Redirecting Crystal/Molecular Structures of Inorganic–Organic Hybrids Based on Lacunary Keggin-Type Polyoxometalates." Molecules 26, no. 19 (2021): 5994. http://dx.doi.org/10.3390/molecules26195994.
Full textAbstract:
Lacunary polyoxometalates (LPOMs) are key precursors for the synthesis of functional POMs. To date, reviews dedicated to behavioral studies of LPOMs often comprise the role of metal ions, including transition metal (TM) and rare earth (RE) ions, in extending and stability of high-nuclearity clusters. In contrast, the role of organic ligands in the structures and properties of lacunary-based hybrids has remained less explored. In this review, we focus on the role of organic fragments in the self-assembling process of POM-based architectures and discuss relationships between the nature and structure of organic ligand and properties such as the topology of hybrid inorganic–organic material in RE and TM-RE heterometallic derivatives of lacunary Keggin-type POMs. The effects of organic fragment in mixed ligand hybrids are also briefly reviewed.
29
Mola, Joaquim, David Pujol, Montserrat Rodríguez, et al. "Synthesis and Structure of Novel RuII - N≡C - Me Complexes and their Activity Towards Nitrile Hydrolysis: An Examination of Ligand Effects." Australian Journal of Chemistry 62, no. 12 (2009): 1675. http://dx.doi.org/10.1071/ch08563.
Full textAbstract:
The synthesis and isolation of new RuII–acetonitrile complexes, of general formula trans,fac-[Ru(bpea)(B)(MeCN)](BF4)2 (bpea = N,N-bis(2-pyridylmethyl)ethylamine; B = bpy, 2,2′-bipyridine, 4; B = dppe, 1,2-bis(diphenylphosphino)ethane, 5), together with a synthetic intermediate trans,fac-[Ru(NO3)(bpea)(dppe)](BF4), 6, are described. Ru(bpea)Cl3, 1, is used as the starting material for the synthesis of all complexes 2–6 presented in this paper, which are characterized by analytical, spectroscopic (IR, UV/Vis, 1D and 2D NMR), and electrochemical techniques (cyclic voltammetry). Furthermore, complexes 4, 5, and 6 have also been characterized in the solid state by single crystal X-ray diffraction analysis. Their structures show a distorted octahedral geometry where the bpea ligand binds in a facial mode, the bidentate ligands bpy and dppe bind in a chelate manner, and finally the MeCN or the NO3 – ligand occupy the sixth position of the octahedral Ru metal centre. The kinetics of the basic hydrolysis of the coordinated MeCN ligand for complexes 4 and 5 and for the related complex [Ru(phen)(MeCN)([9]aneS3)](BF4)2, 7, which contains the 1,4,7-trithiacyclonane ligand ([9]aneS3) and 1,10-phenanthroline (phen) is also described. Second-order rate constants for acetonitrile hydrolysis measured at 25°C of k = 1.01 × 10–3 M–1 s–1 for 4, 1.08 × 10–4 M–1 s–1 for 5, and 6.8 × 10–3 M–1 s–1 for 7, have been obtained through UV-vis spectroscopy. Activation parameters have also been determined over the temperature range 25.0–45.0°C and agree with a mechanism that involves an associative rate-determining step. Finally the electronic and steric influence of the auxiliary ligands on this reaction for the above and related complexes is discussed.
30
Kirkland, Justin K., Shahriar N. Khan, Bryan Casale, Evangelos Miliordos, and Konstantinos D. Vogiatzis. "Ligand field effects on the ground and excited states of reactive FeO2+ species." Physical Chemistry Chemical Physics 20, no. 45 (2018): 28786–95. http://dx.doi.org/10.1039/c8cp05372c.
Full textAbstract:
Multiconfigurational quantum chemical calculations on bare and representative ligated iron oxide dicationic species suggest that weak ligand fields promote more reactive channels, whereas strong ligand fields stabilize the less reactive iron-oxo structure.
31
Yi, Ping, Mark D. Driscoll, Jing Huang та ін. "The Effects of Estrogen-Responsive Element- and Ligand-Induced Structural Changes on the Recruitment of Cofactors and Transcriptional Responses by ERα and ERβ". Molecular Endocrinology 16, № 4 (2002): 674–93. http://dx.doi.org/10.1210/mend.16.4.0810.
Full textAbstract:
Abstract Estrogen signaling is mediated by ERα and -β. ERs are converted from an inactive form to a transcriptionally active state through conformational changes induced by ligand and estrogen-responsive element (ERE) sequences. We show here that ERα and ERβ bind to an ERE independently from ER ligands. We found that although the binding affinity of ERβ for an ERE is 2-fold lower than that of ERα, both ERs use the same nucleotides for DNA contacts. We show that both EREs and ligands are independent modulators of ER conformation. Specifically, the ERE primarily determines the receptor-DNA affinity, whereas the structure of the ER ligand dictates the affinity of ER for particular cofactors. We found that the ligand-dependent cofactor transcriptional intermediary factor-2, through a distinct surface, also interacts with ERα preferentially and independently of ligand. The extent of interaction, however, is dependent upon the ER-ERE affinity. In transfected cells, ERα is more transcriptionally active than ERβ. The ERE sequence, however, determines the potency of gene induction when either ER subtype binds to an agonist. Antagonists prevent ERs from inducing transcription independently from ERE sequences. Thus, ERE- and ligand-induced structural changes are independent determinants for the recruitment of cofactors and transcriptional responses. The ability of ERα to differentially recruit a cofactor could contribute to ER subtype-specific gene responses.
32
Mikata, Yuji, Yasuko Kuroda, Kyoko Naito та ін. "Structure and electrochemical properties of (μ-O)2Mn2(iii,iii) and (μ-O)2Mn2(iii,iv) complexes supported by pyridine-, quinoline-, isoquinoline- and quinoxaline-based tetranitrogen ligands". Dalton Transactions 50, № 12 (2021): 4133–44. http://dx.doi.org/10.1039/d1dt00184a.
Full textAbstract:
A systematic comparison of a total of 14 complexes bearing a (μ-O)<sub>2</sub>Mn<sub>2</sub> core with tetranitrogen ligands reveals small but solid relationships between structural parameters and redox potentials induced by ligand effects.
33
Mahmud, Sakib, Samina Akhter, Md Atiar Rahman, et al. "Antithrombotic Effects of Five Organic Extracts of Bangladeshi PlantsIn Vitroand Mechanisms inIn SilicoModels." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/782742.
Full textAbstract:
This research was carried out to investigate the thrombolytic effects of the methanolic extracts of five Bangladeshi plants. Phytochemical metabolites of those plants have been identified to elucidate whether the plant-derived metabolites are linked with the thrombolytic effects. Potential computer aided models were adopted in this study to find out a structure-function correlation between the phytochemical constituents and thrombolytic effects using the secondary metabolites as ligands and tissue plasminogen activator (t-PA) as receptor for the best fit ligand-receptor interaction.
34
DIEHL, CHRISTINA, and HELMUT SCHLAAD. "Glycopolyoxazoline-lectin interactions. Effects of ligand structure on clustering kinetics." Polimery 58, no. 9 (2013): 650–53. http://dx.doi.org/10.14314/polimery.2013.650.
Full text
35
Alyea, Elmer C., George Ferguson, John Malito, and Barbara L. Ruhl. "Cyclopalladation of trimesitylarsine. The X-ray crystal structure for." Canadian Journal of Chemistry 66, no. 12 (1988): 3162–65. http://dx.doi.org/10.1139/v88-488.
Full textAbstract:
The bulky trimesitylarsine ligand, As(mes)3, undergoes facile cyclopalladation to yield the dimeric complex, [Formula: see text], characterized by microanalysis, IR and 1H NMR spectroscopy. This complex is very stable but readily undergoes bridge-cleavage reactions with tertiary phosphine ligands having ligand cone angles less than 170°. The crystal structure for the PPh3 bridge-cleavage product is reported. This complex, [Formula: see text] is monoclinic, space group P21/c with a = 20.469(2), b = 12.702(2), c = 15.401(4) Å, β = 98.46(1)°, V = 3961 Å3Z = 4, R = 0.0284 and Rw = 0.0305. The Pd geometry is distorted square-planar with principal dimensions, Pd—Cl 2.395(1), Pd—P 2.318(1), Pd—C 2.056(3), and Pd—As 2.437(1) Å; As—Pd—Cl 96.5(1), Cl—Pd—P 90.9(1), P—Pd—C 93.7(1), As—Pd—C 78.9(1), As—Pd—P 172.6(1), and Cl—Pd—C 171.7(1)°. The average C—P—C angle (104.3(1)°) is smaller than expected and is rationalized on the basis of steric effects operative within the complex.
36
Williams, Wynford R. "Dampening of neurotransmitter action: molecular similarity within the melatonin structure." Endocrine Regulations 52, no. 4 (2018): 199–207. http://dx.doi.org/10.2478/enr-2018-0025.
Full textAbstract:
AbstractObjectives. Melatonin initiates physiologic and therapeutic responses in various tissues through binding to poorly defined MT receptors regulated by G-proteins and purine nucleotides. Melatonin’s interaction with other G-protein regulated receptors, including those of serotonin, is unclear. This study explores the potential for the interaction of melatonin with nucleotide and receptor ligand structures. Methods. The study uses a computational program to investigate relative molecular similarity by the comparative superimposition and quantitative fitting of molecular structures to adenine and guanine nucleotide templates. Results. A minimum energy melatonin conformer replicates the nucleotide fits of ligand structures that regulate Gαi and Gαq proteins via serotonin, dopamine, opioid, α-adrenoceptor, and muscarinic receptor classes. The same conformer also replicates the nucleotide fits of ligand structures regulating K+ and Ca2+ ion channels. The acyl-methoxy distance within the melatonin conformer matches a carbonyl-hydroxyl distance in guanine nucleotide. Conclusion. Molecular similarity within the melatonin and ligand structures relates to the established effects of melatonin on cell receptors regulated by purine nucleotides in cell signal transduction processes. Pharmacologic receptor promiscuity may contribute to the widespread effects of melatonin.
37
Ma, Zhifeng, Naoki Nakatani, Hiroshi Fujii, and Masahiko Hada. "DFT insight into axial ligand effects on electronic structure and mechanistic reactivity of oxoiron(iv) porphyrin." Physical Chemistry Chemical Physics 22, no. 21 (2020): 12173–79. http://dx.doi.org/10.1039/d0cp01867h.
Full text
38
Wen, Zhao, Changjiang Wu, Jian Chen, Shuzhang Qu, Xinwei Li, and Wei Wang. "Homogeneous Non-Metallocene Group 4 Metals Ligated with [N,N] Bidentate Ligand(s) for Olefin Polymerization." Polymers 16, no. 3 (2024): 406. http://dx.doi.org/10.3390/polym16030406.
Full textAbstract:
The development of catalysts has significantly advanced the progress of polyolefin materials. In particular, group 4 (Ti, Zr, Hf) non-metallocene catalysts ligated with [N,N] bidentate ligand(s) have garnered increasing attention in the field of olefin polymerization due to their structurally stability and exceptional polymerization behaviors. Ligands containing nitrogen donors are diverse and at the core of many highly active catalysts. They mainly include amidine, guanidinato, diamine, and various N-heterocyclic ligands, which can be used to obtain a series of new polyolefin materials, such as ultrahigh molecular weight polyethylene (UHWMPE), olefin copolymers (ethylene/norbornene and ethylene/α-olefin) with high incorporations, and high isotactic or syndiotactic polypropylene after coordination with group 4 metals and activation by cocatalysts. Herein, we focus on the advancements and applications of this field over the past two decades, and introduce the catalyst precursors with [N,N] ligand(s), involving the effects of ligand structure, cocatalyst selection, and polymerization conditions on the catalytic activity and polymer properties.
39
Horváth, István, Norbert Jeszenői, Mónika Bálint, Gábor Paragi, and Csaba Hetényi. "A Fragmenting Protocol with Explicit Hydration for Calculation of Binding Enthalpies of Target-Ligand Complexes at a Quantum Mechanical Level." International Journal of Molecular Sciences 20, no. 18 (2019): 4384. http://dx.doi.org/10.3390/ijms20184384.
Full textAbstract:
Optimization of the enthalpy component of binding thermodynamics of drug candidates is a successful pathway of rational molecular design. However, the large size and missing hydration structure of target-ligand complexes often hinder such optimizations with quantum mechanical (QM) methods. At the same time, QM calculations are often necessitated for proper handling of electronic effects. To overcome the above problems, and help the QM design of new drugs, a protocol is introduced for atomic level determination of hydration structure and extraction of structures of target-ligand complex interfaces. The protocol is a combination of a previously published program MobyWat, an engine for assigning explicit water positions, and Fragmenter, a new tool for optimal fragmentation of protein targets. The protocol fostered a series of fast calculations of ligand binding enthalpies at the semi-empirical QM level. Ligands of diverse chemistry ranging from small aromatic compounds up to a large peptide helix of a molecular weight of 3000 targeting a leukemia protein were selected for systematic investigations. Comparison of various combinations of implicit and explicit water models demonstrated that the presence of accurately predicted explicit water molecules in the complex interface considerably improved the agreement with experimental results. A single scaling factor was derived for conversion of QM reaction heats into binding enthalpy values. The factor links molecular structure with binding thermodynamics via QM calculations. The new protocol and scaling factor will help automated optimization of binding enthalpy in future molecular design projects.
40
Jang, Yongwoo, Woori Kim, Pierre Leblanc, Chun-Hyung Kim, and Kwang-Soo Kim. "Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1." Experimental & Molecular Medicine 53, no. 1 (2021): 19–29. http://dx.doi.org/10.1038/s12276-021-00555-5.
Full textAbstract:
AbstractUntil recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.
41
Navarro, Miquel, Mo Li, Stefan Bernhard, and Martin Albrecht. "A mesoionic nitrogen-donor ligand: structure, iridium coordination, and catalytic effects." Dalton Transactions 47, no. 3 (2018): 659–62. http://dx.doi.org/10.1039/c7dt04555g.
Full textAbstract:
A first example of a mesoionic ligand with a nitrogen coordination site was prepared by a simple and robust synthesis and is shown to have excellent properties for promoting iridium-catalyzed water oxidation.
42
Świderski, Grzegorz, Ewelina Gołębiewska, Natalia Kowalczyk, et al. "Structure, Antioxidant Activity and Antimicrobial Study of Light Lanthanide Complexes with p-Coumaric Acid." Materials 17, no. 6 (2024): 1324. http://dx.doi.org/10.3390/ma17061324.
Full textAbstract:
This paper presents the results of a study of the effects of the lanthanide ions Ce3+, Pr3+, Nd3+ and Sm3+ on the electronic structure and antioxidant and biological (antimicrobial and cytotoxic) properties of p-coumaric acid (p-CAH2). Structural studies were conducted via spectroscopic methods (FTIR, ATR, UV). Thermal degradation studies of the complexes were performed. The results are presented in the form of TG, DTG and DSC curves. Antioxidant properties were determined via activity tests against DPPH, ABTS and OH radicals. The reducing ability was tested via CUPRAC assays. Minimum inhibitory concentrations (MICs) of the ligand and lanthanide complexes were determined on E. coli, B. subtilis and C. albicans microorganisms. The antimicrobial activity was also determined using the MTT assay. The results were presented as the relative cell viability of C. albicans, P. aeruginosa, E. coli and S. aureus compared to controls and expressed as percentages. In the obtained complexes in the solid phase, lanthanide ions coordinate three ligands in a bidentate chelating coordination mode through the carboxyl group of the acid. Spectroscopic analysis showed that lanthanide ions increase the aromaticity of the pi electron system of the ligand. Thermal analysis showed that the complexes are hydrated and have a higher thermal stability than the ligand. The products of thermal decomposition of the complexes are lanthanide oxides. In the aqueous phase, the metal combines with the ligand in a 1:1 molar ratio. Antioxidant activity tests showed that the complexes have a similar ability to remove free radicals. ABTS and DPPH tests showed that the complexes have twice the ability to neutralise radicals than the ligand, and a much higher ability to remove the hydroxyl radical. The abilities of the complexes and the free ligand to reduce Cu2+ ions in the CUPRAC test are at a similar level. Lanthanide complexes of p-coumaric acid are characterised by a higher antimicrobial capacity than the free ligand against Escherichia coli bacteria, Bacillus subtilis and Candida albicans fungi.
43
Bukhdruker, Sergey, Tatsiana Varaksa, Philipp Orekhov, et al. "Structural insights into the effects of glycerol on ligand binding to cytochrome P450." Acta Crystallographica Section D Structural Biology 79, no. 1 (2023): 66–77. http://dx.doi.org/10.1107/s2059798322011019.
Full textAbstract:
New antitubercular drugs are vital due to the spread of resistant strains. Carbethoxyhexyl imidazole (CHImi) inhibits cytochrome P450 CYP124, which is a steroid-metabolizing enzyme that is important for the survival of Mycobacterium tuberculosis in macrophages. The available crystal structure of the CYP124–CHImi complex reveals two glycerol molecules in the active site. A 1.15 Å resolution crystal structure of the glycerol-free CYP124–CHimi complex reported here shows multiple conformations of CHImi and the CYP124 active site which were previously restricted by glycerol. Complementary molecular dynamics simulations show coherence of the ligand and enzyme conformations. Spectrophotometric titration confirmed the influence of glycerol on CHImi binding: the affinity decreases more than tenfold in glycerol-containing buffer. In addition, it also showed that glycerol has a similar effect on other azole and triazole CYP124 ligands. Together, these data show that glycerol may compromise structural–functional studies and impede rational drug-design campaigns.
44
Roupa, Ioanna, Michael Kaplanis, Catherine Raptopoulou та ін. "Crystal structure of fac-aqua[(E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline-κ2 N,N′]tricarbonylrhenium(I) hexafluoridophosphate methanol monosolvate". Acta Crystallographica Section E Crystallographic Communications 75, № 5 (2019): 580–84. http://dx.doi.org/10.1107/s2056989019004298.
Full textAbstract:
In the title compound, fac-[Re(C19H13N3S)(CO)3(H2O)]PF6·CH3OH, the coordination environment of the ReI atom is octahedral with a C3N2O coordination set. In this molecule, the N,N′ bidentate ligand, (E)-4-(benzo[d]thiazol-2-yl)-N-(pyridin-2-ylmethylidene)aniline, and the monodentate aqua ligand occupy the three available coordination sites of the [Re(CO)3]+ core, generating a `2 + 1' mixed-ligand complex. In this complex, the Re—C bonds of the carbonyl ligands trans to the coordinating N,N′ atoms of the bidentate ligand are longer than the Re—C bond of the carbonyl group trans to the aqua ligand, in accordance with the intensity of their trans effects. The complex is positively charged with PF6 − as the counter-ion. In the structure, the complexes form dimers through π–π intermolecular interactions. O—H...O and O—H...N hydrogen bonds lead to the formation of stacks parallel to the a axis, which further extend into layers parallel to (0\overline{1}1). Through O—H...F hydrogen bonds between the complexes and the PF6 −counter-anions, a three-dimensional network is established.
45
Borbulevych, Oleg, Roger I. Martin, and Lance M. Westerhoff. "High-throughput quantum-mechanics/molecular-mechanics (ONIOM) macromolecular crystallographic refinement withPHENIX/DivCon: the impact of mixed Hamiltonian methods on ligand and protein structure." Acta Crystallographica Section D Structural Biology 74, no. 11 (2018): 1063–77. http://dx.doi.org/10.1107/s2059798318012913.
Full textAbstract:
Conventional macromolecular crystallographic refinement relies on often dubious stereochemical restraints, the preparation of which often requires human validation for unusual species, and on rudimentary energy functionals that are devoid of nonbonding effects owing to electrostatics, polarization, charge transfer or even hydrogen bonding. While this approach has served the crystallographic community for decades, as structure-based drug design/discovery (SBDD) has grown in prominence it has become clear that these conventional methods are less rigorous than they need to be in order to produce properly predictive protein–ligand models, and that the human intervention that is required to successfully treat ligands and other unusual chemistries found in SBDD often precludes high-throughput, automated refinement. Recently, plugins to thePython-based Hierarchical ENvironment for Integrated Xtallography(PHENIX) crystallographic platform have been developed to augment conventional methods with thein situuse of quantum mechanics (QM) applied to ligand(s) along with the surrounding active site(s) at each step of refinement [Borbulevychet al.(2014),Acta CrystD70, 1233–1247]. This method (Region-QM) significantly increases the accuracy of the X-ray refinement process, and this approach is now used, coupled with experimental density, to accurately determine protonation states, binding modes, ring-flip states, water positions and so on. In the present work, this approach is expanded to include a more rigorous treatment of the entire structure, including the ligand(s), the associated active site(s) and the entire protein, using a fully automated, mixed quantum-mechanics/molecular-mechanics (QM/MM) Hamiltonian recently implemented in theDivConpackage. This approach was validated through the automatic treatment of a population of 80 protein–ligand structures chosen from the Astex Diverse Set. Across the entire population, this method results in an average 3.5-fold reduction in ligand strain and a 4.5-fold improvement inMolProbityclashscore, as well as improvements in Ramachandran and rotamer outlier analyses. Overall, these results demonstrate that the use of a structure-wide QM/MM Hamiltonian exhibits improvements in the local structural chemistry of the ligand similar to Region-QM refinement but with significant improvements in the overall structure beyond the active site.
46
Kuhn, Bernd, Jens-Uwe Peters, Markus G. Rudolph, Peter Mohr, Martin Stahl, and Andreas Tosstorff. "Details Matter in Structure-based Drug Design." CHIMIA 77, no. 7/8 (2023): 489. http://dx.doi.org/10.2533/chimia.2023.489.
Full textAbstract:
Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.
47
Dickerhoff, Jonathan, Jixun Dai, and Danzhou Yang. "Abstract 3840: High-resolution structural insights into targeting the MYC oncogene G-quadruplex with the quinoline derivative PEQ." Cancer Research 83, no. 7_Supplement (2023): 3840. http://dx.doi.org/10.1158/1538-7445.am2023-3840.
Full textAbstract:
Abstract The transcription of the MYC oncogene, a central player of oncogenesis, is strongly controlled by DNA G-quadruplexes in its promoter region (MycG4). Stabilization of MycG4 with small molecules downregulates MYC expression and has devastating effects on many cancers. Thus, targeting MycG4 is an attractive anti-cancer strategy especially since the MYC protein is considered a very difficult target. DNA G-quadruplexes are four-stranded secondary structures and enriched in promoters of oncogenes. Their globular shape and high structural diversity distinguishes them from the thread-like and uniform DNA duplex ubiquitously found in the cell. High-resolution structures reveal the molecular interactions between ligands and G-quadruplexes and are the key for structure-based rational design of new and improved drugs. Here, we present the new MycG4 binder PEQ, a quinoline derivative, and describe its molecular recognition of the MycG4. PEQ is more drug-like than many prominent G-quadruplex binder because it lacks an extensive aromatic moiety. Most of the reported G-quadruplex binding ligands include extended and rigid aromatic moieties with less drug-like properties. We used solution NMR and molecular dynamics calculations to first determine the high-resolution structures of the unbound wild-type MycG4, and next structures of PEQ in complex to wild-type MycG4 or the most commonly studied modified MycG4. This modified MycG4 sequence bears a mutated residue in the binding pocket that is critical for ligand interactions. PEQ binds the MycG4 with a 2:1 stoichiometry and stacks on the G-quadruplex ends. Specific binding pockets are formed in which a flanking residue is recruited by the PEQ to form a joint-plane. The identity of the recruited residue controls the orientation of the ligand and the resulting interactions, as shown by structural comparison of PEQ in complex with either the wild-type or mutated MycG4. Including the PEQ structure, four ligand-MycG4 complexes are now available and we performed the first systematic analysis. We show that despite the dynamic character of the flanking sequences, all ligands recruit DNA bases in a conserved and sequence-specific manner. Moreover, we propose the design of complementary hydrogen bonds to match the recruited DNA base with a drug via structure-based rational design. In conclusion, our work introduces the quinoline PEQ as new lead compound for cancer therapeutics targeting MYC through the MycG4. We present the MycG4-ligand structure with wild-type binding sites as more accurate target and identify important aspects of ligand binding to guide future design of cancer therapeutics. Citation Format: Jonathan Dickerhoff, Jixun Dai, Danzhou Yang. High-resolution structural insights into targeting the MYC oncogene G-quadruplex with the quinoline derivative PEQ. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3840.
48
Hung, Che-Lun, and Guan-Jie Hua. "Cloud Computing for Protein-Ligand Binding Site Comparison." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/170356.
Full textAbstract:
The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.
49
Cuadrado, Irene, Ángel Amesty, Juan Cedrón, et al. "Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses." Molecules 23, no. 12 (2018): 3197. http://dx.doi.org/10.3390/molecules23123197.
Full textAbstract:
A series of nine derivatives (2–10) were prepared from the diterpene solidagenone (1) and their structures were elucidated by means of spectroscopic studies. Their ability to inhibit inflammatory responses elicited in peritoneal macrophages by TLR ligands was investigated. Compounds 5 and 6 showed significant anti-inflammatory effects, as they inhibited the protein expression of nitric oxide synthase (NOS-2), cyclooxygenase-2 (COX-2), and cytokine production (TNF-α, IL-6, and IL-12) induced by the ligand of TLR4, lipopolysaccharide (LPS), acting at the transcriptional level. Some structure–activity relationships were outlined. Compound 5 was selected as a representative compound and molecular mechanisms involved in its biological activity were investigated. Inhibition of NF-κB and p38 signaling seems to be involved in the mechanism of action of compound 5. In addition, this compound also inhibited inflammatory responses mediated by ligands of TLR2 and TLR3 receptors. To rationalize the obtained results, molecular docking and molecular dynamic studies were carried out on TLR4. All these data indicate that solidagenone derivative 5 might be used for the design of new anti-inflammatory agents.
50
Yang, En-Cui, Qing-Qing Liang, Xiu-Guang Wang, and Xiao-Jun Zhao. "Two Novel Triazole-Based Metal - Organic Frameworks Consolidated by a Flexible Dicarboxylate Co-ligand: Hydrothermal Synthesis, Crystal Structure, and Luminescence Properties." Australian Journal of Chemistry 61, no. 10 (2008): 813. http://dx.doi.org/10.1071/ch08147.
Full textAbstract:
To explore the effects of a co-ligand on the construction of mixed-ligand metal–organic frameworks (MOFs), two new triazole-based complexes with a flexible dicarboxylate as a co-ligand, {[Zn4(trz)4(gt)2(H2O)2](H2O)2}n 1 and {[Cd2(trz)2(gt)(H2O)2](H2O)4}n 2 (Htrz = 1,2,4-triazole; H2gt = glutaric acid), were synthesized and their structures were fully characterized by elemental analyses, IR spectroscopy, and single-crystal X-ray crystallography. Their thermal stability and luminescence emissions were further investigated to establish their structure–property relationship. Crystal structure determination showed that 1 is a neutral two-dimensional pillared-bilayer network consisting of 14-membered hydrophobic channels, whereas 2 is an infinite three-dimensional framework constructed from tetranuclear [Cd4(trz)4]4+ subunits. Interestingly, the overall structure of both MOFs can be solely supported by ZnII/CdII and trz anions, and were further consolidated by the introduction of a flexible gt co-ligand. In addition, the carboxylate groups in the co-ligand can also serve as a weak O–H···O hydrogen-bond acceptor to capture guest water molecules. The synchronous weight-loss behaviour of trz and gt anions presented by thermogravometric curves suggest their cooperative contributions to the thermal stability of the MOFs. In contrast, the fluorescence emissions of two complexes are significantly dominated by the core trz ligand, rather than the gt co-ligand and metal ions.