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1
Jaroch, Stefan, and Hilmar Weinmann. "Putting small molecules in the lead." Nature Chemical Biology 1, no. 4 (2005): 180–83. http://dx.doi.org/10.1038/nchembio0905-180.
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Li, Qingxin, and CongBao Kang. "Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery." International Journal of Molecular Sciences 21, no. 15 (2020): 5262. http://dx.doi.org/10.3390/ijms21155262.
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Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.
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Loriamini, Melika, Melissa M. Lewis-Bakker, Kayluz Frias Boligan, et al. "Small Molecule Drugs That Inhibit Phagocytosis." Molecules 28, no. 2 (2023): 757. http://dx.doi.org/10.3390/molecules28020757.
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In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity. We recently screened a chemical library of 80 compounds containing pyrazole/isoxazole/pyrrole core structures and found four hit molecules for further follow-up, all having the pyrazole core structure. Subsequent evaluation via MTT viability, LDH release, and apoptosis, led to the selection of two lead compounds with negligible toxicity and high efficacy. In an in vitro assay for inhibition of phagocytosis, their IC50 values were 2–4 µM. The rational development of these discoveries from hit to lead molecule stage, viz. independent synthesis/scale up of hit molecules, and in vivo activities in mouse models of autoimmune disease, will result in the selection of a lead compound(s) for further pre-clinical evaluation.
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Deepak, G., A. Dinakara Rao Dr., and Babu Khan Mohammad. "Identifying Potential Bace-1 Enzyme Inhibitors /Lead Small Molecules: Relevance to Alzheimer's Diseases." Identifying Potential Bace-1 Enzyme Inhibitors /Lead Small Molecules: Relevance to Alzheimer's Diseases 10, no. 10 (2022): D586—D587. https://doi.org/10.6084/m9.figshare.21436593.
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It is unclear what causes Alzheimer's disease. However, genetic data support the amyloid hypothesis, which states that abnormal beta-amyloid protein aggregation initiates the illness process. There is a lengthy pre-clinical stage of Alzheimer's disease. The terrible consequences of amyloidogenic diseases like Alzheimer's. More than 7000 tiny molecules have been screened from ZINC subsets and exposed to 165 compounds and 16. From a research perspective, I have examined numerous databases like the ZINC Subset, PubChem compound database, and Drug bank database. For docking investigations, these processed molecules were employed. The docking study enabled us to locate a small number of compounds with good inhibitory interactions with the protein, i.e., chemicals that impede the protein's function. These final compounds underwent drug-likeness testing and methods for ADME descriptor validation. These substances or molecules may help develop potent medications to treat Alzheimer's. To determine which protein had the lowest energy conformation and was, therefore, the most stable, a molecular dynamic of the protein was run.
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Berzins, Agris, and Andris Actins. "Crystal structures of two molecules with small chemical structure difference." Acta Crystallographica Section A Foundations and Advances 70, a1 (2014): C1686. http://dx.doi.org/10.1107/s2053273314083132.
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Droperidol and benperidol, neuroleptic pharmaceuticals, both are used as antipsychotics. The chemical structure of these two compounds differs only by one double bond in the middle of the molecule (see Scheme). It is known that both of these substances can form several polymorphs and solvates. Crystal structures of most of these phases are known [1, 2]. Despite the molecular structure similarities, there are no known droperidol polymorph or solvate isostructural to those of benperidol. Although there has been studies characterizing the crystal structures of chemically very similar compounds, general explanation to observed structural differences was not found (e.g. [3]). In this study we analyse the crystal structures of benperidol and droperidol by comparing the molecule conformation and packing in crystal structures of both of these compounds. Molecule conformation is compared and torsion angles which differ and therefore lead to different crystal structures are identified. Theoretical calculation of potential energy surfaces of these torsion angles are performed in Gaussian09. Intermolecular interactions and molecule packing in all crystal structures are compared by trying to understand the general differences between both molecules. Analysis of structures deposited in Cambridge Structural Database is performed to find conformations and intermolecular interactions characteristic for similar molecules by therefore trying to generalize structural formation possibilities for both pharmaceuticals and understand the reasons for crystallization of only observed structures. Theoretical calculations of benperidol and droperidol crystal structures where benperidol molecules are replaced by droperidol and vice versa are performed in CASTEP to compare the energy of experimentally observed crystal structure with that of theoretically possible structure isostructural to double-bond-different molecule.
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Gregson, Aaron, Kaitlyn Thompson, Stella E. Tsirka, and David L. Selwood. "Emerging small-molecule treatments for multiple sclerosis: focus on B cells." F1000Research 8 (March 1, 2019): 245. http://dx.doi.org/10.12688/f1000research.16495.1.
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Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell–directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.
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George, Dare E., and Jetze J. Tepe. "Advances in Proteasome Enhancement by Small Molecules." Biomolecules 11, no. 12 (2021): 1789. http://dx.doi.org/10.3390/biom11121789.
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The proteasome system is a large and complex molecular machinery responsible for the degradation of misfolded, damaged, and redundant cellular proteins. When proteasome function is impaired, unwanted proteins accumulate, which can lead to several diseases including age-related and neurodegenerative diseases. Enhancing proteasome-mediated substrate degradation with small molecules may therefore be a valuable strategy for the treatment of various neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. In this review, we discuss the structure of proteasome and how proteasome’s proteolytic activity is associated with aging and various neurodegenerative diseases. We also summarize various classes of compounds that are capable of enhancing, directly or indirectly, proteasome-mediated protein degradation.
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Kretić, Danijela S., Marija I. Maslarević, and Dušan Ž. Veljković. "Small Deviations in Geometries Affect Detonation Velocities and Pressures of Nitroaromatic Molecules." Organics 6, no. 2 (2025): 17. https://doi.org/10.3390/org6020017.
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Understanding the factors that affect the detonation performance of high-energy molecules (HEMs) is crucial for the design of novel explosives and fuels with desirable characteristics. While molecular factors, such as the presence of specific functional groups that give organic molecules explosive properties, are key determinants of detonation characteristics, other factors like the geometry of molecules in crystal structures can also affect the high-energy properties of materials. Although it is known that slight deviations in the crystal structure geometry affect the sensitivity of nitroaromatic explosives, the influence of these variations on detonation performance remains unknown. In this study, we extracted different crystal structures of the same high-energy nitroaromatic molecules from the Cambridge Structural Database and calculated their detonation velocities and pressures using the Kamlet–Jacobs equations. Results indicated that different geometries of the same crystal structure can lead to non-negligible differences in detonation velocities and pressures. In the case of the 2,4,6-triamino-1,3,5-trinitrobenzene molecule, discrepancies in detonation pressures among different crystal structures were calculated to be 7.68%. Analysis of geometrical arrangements showed that these differences are mainly the consequence of diverse non-covalent bonding patterns that affect crystal densities.
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Godbole, Adwait Anand, Wareed Ahmed, Rajeshwari Subray Bhat, Erin K. Bradley, Sean Ekins, and Valakunja Nagaraja. "Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors." Antimicrobial Agents and Chemotherapy 59, no. 3 (2014): 1549–57. http://dx.doi.org/10.1128/aac.04516-14.
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ABSTRACTWe describe inhibition ofMycobacterium tuberculosistopoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of bothMycobacterium smegmatisandM. tuberculosiscells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison theM. tuberculosisandM. smegmatistopoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.
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Alvarez-Gonzalez, Juan Antonio, Robert Maul, Rahul M. Kohli, and Patricia J. Gearhart. "Small molecule inhibitors of Activation-Induced Deaminase." Journal of Immunology 200, no. 1_Supplement (2018): 48.18. http://dx.doi.org/10.4049/jimmunol.200.supp.48.18.
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Abstract Activation-Induced Deaminase (AID) is a cytosine deaminase that converts cytosine into uracil in DNA, which initiates a cascade of mutagenic DNA repair to introduce point mutations and double-strand breaks. Specific targeting of AID to the immunoglobulin heavy chain locus promotes somatic hypermutation in antibody variable genes for affinity maturation, and breaks in switch regions for class switch recombination (CSR). However, mis-targeting of AID to other loci could initiate tumor development and lead to greater drug resistance among cancer cells when continually expressed. To identify a small molecule inhibitor of AID, we screened ~400,000 compounds in conjunction with the NCATS core facility at NIH. Using FRET based analysis of cytosine deamination, we identified 150 potential inhibitors of AID catalytic activity. To confirm biological function, we examined their effects on CSR in an in vitro murine B-cell activation assay using CH12 cells, wherein 30 were confirmed inhibitor candidates. We then selected the top seven molecules to proceed with further characterization in wild type primary splenocytes, and found two near-identical compounds that had inhibitory activity. From these structures, we tested commercially available analogues and identified two molecules with inhibitory efficacy in the nanomolar range. Using these approaches, we hope to identify a small molecule with great efficacy and low toxicity for use as a molecular probe to further characterize AID’s intricacies, or even as a therapeutic agent.
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Sui, Xin, Man Pan, and Yi-Ming Li. "Insights into the Design of p97-targeting Small Molecules from Structural Studies on p97 Functional Mechanism." Current Medicinal Chemistry 27, no. 2 (2020): 298–316. http://dx.doi.org/10.2174/0929867326666191004162411.
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p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget’s disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small-molecule inhibitors have been deployed against p97, including bis (diethyldithiocarbamate)- copper and CB-5083, which entered the first phase of clinical tests but failed. One bottleneck in the design of p97 drugs is that its molecular mechanism remains unclear. This paper summarizes recent studies on the molecular mechanisms of p97, which may lead to insight into how the next generation of small molecules targeting p97 can be designed.
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Norel, R., H. J. Wolfson, and R. Nussinov. "Small Molecule Recognition: Solid Angles Surface Representation and Molecular Shape Complementarity." Combinatorial Chemistry & High Throughput Screening 2, no. 4 (1999): 223–36. http://dx.doi.org/10.2174/1386207302666220204193837.
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Abstract: Here we examine the recognition of small molecules by their protein and DNA receptors. We focus on two questions: First, how well does the solid angle molecular surface representation perform in fitting together the surfaces of small ligands, such as drugs and cofactors to their corresponding receptors; And second, in particular, to what extent does the shape complementarity play a role in the matching (recognition) process of such small molecules. Both questions have been investigated in protein-protein binding: "Critical Points" based on solid angle calculations have been shown to perform well in the matching of large protein molecules. They are robust, may be few in numbers, and capture satisfactorily the molecular shape. Shape complementarity has been shown to be a critical factor in protein protein recognition, but has not been examined in drug-receptor recognition. To probe these questions, here we dock 185 receptor-small ligand molecule pairs. We find that such a representation performs adequately for the smaller ligands too, and that shape complementarity is also observed. These issues are important, given the large databases of drugs that routinely have to be scanned to find candidate, lead compounds. We have been able to carry out such large scale docking experiments owing to our efficient, computer-vision based docking algorithms. Its fast CPU matching times, on the order of minutes on a PC, allows such large scale docking experiments.
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Ursu, Andrei, Jessica L. Childs-Disney, Ryan J. Andrews, et al. "Design of small molecules targeting RNA structure from sequence." Chemical Society Reviews 49, no. 20 (2020): 7252–70. http://dx.doi.org/10.1039/d0cs00455c.
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Saftić, Dijana, Željka Ban, Josipa Matić, Lidija-Marija Tumirv, and Ivo Piantanida. "Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications." Current Medicinal Chemistry 26, no. 30 (2019): 5609–24. http://dx.doi.org/10.2174/0929867325666180508090640.
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: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.
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Zubair, Tanzida, and Debasish Bandyopadhyay. "Small Molecule EGFR Inhibitors as Anti-Cancer Agents: Discovery, Mechanisms of Action, and Opportunities." International Journal of Molecular Sciences 24, no. 3 (2023): 2651. http://dx.doi.org/10.3390/ijms24032651.
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Epidermal growth factor receptors (EGFRs) are a class of receptor tyrosine kinase that are also called ErbB1 and HER1. EGFR tyrosine kinase activity inhibition is considered a promising therapeutic strategy for the treatment of cancer. Many small-molecule inhibitors of EGFR tyrosine kinase (EGFR-TK), from medicinally privileged molecules to commercial drugs, have been overviewed. Particular attention has been paid to the structure of the molecule and its mechanism of action if reported. Subsequent classification of the molecules under discussion has been carried out. Both natural and synthetic and reversible and irreversible EGFR-tyrosine kinase inhibitors have been discussed. Various types of cancers that are caused by overexpression of the EGFR gene, their possible molecular origins, and their natures have also been counted in this article. Because the EGFR signaling pathway controls the proliferation, growth, survival, and differentiation of cells, and the mutated EGFR gene overproduces EGFR protein, which ultimately causes several types of cancer, proper understanding of the molecular dynamics between the protein structure and its inhibitors will lead to more effective and selective EGFR-TKIs, which in turn will be able to save more lives in the battle against cancer.
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Zablowsky, Nina, Lydia Farack, Sven Rofall, et al. "High Throughput FISH Screening Identifies Small Molecules That Modulate Oncogenic lncRNA MALAT1 via GSK3B and hnRNPs." Non-Coding RNA 9, no. 1 (2023): 2. http://dx.doi.org/10.3390/ncrna9010002.
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Traditionally, small molecule-based drug discovery has mainly focused on proteins as the drug target. Opening RNA as an additional target space for small molecules offers the possibility to therapeutically modulate disease-driving non-coding RNA targets as well as mRNA of otherwise undruggable protein targets. MALAT1 is a highly conserved long-noncoding RNA whose overexpression correlates with poor overall patient survival in some cancers. We report here a fluorescence in-situ hybridization-based high-content imaging screen to identify small molecules that modulate the oncogenic lncRNA MALAT1 in a cellular setting. From a library of FDA approved drugs and known bioactive molecules, we identified two compounds, including Niclosamide, an FDA-approved drug, that lead to a rapid decrease of MALAT1 nuclear levels with good potency. Mode-of-action studies suggest a novel cellular regulatory pathway that impacts MALAT1 lncRNA nuclear levels by GSK3B activation and the involvement of the RNA modulating family of heterogenous nuclear ribonucleoproteins (hnRNPs). This study is the basis for the identification of novel targets that lead to a reduction of the oncogenic lncRNA MALAT1 in a cancer setting.
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Anand, Kumar, Sayak Khawas, Apurva Singh, Puja kumari, Neha Nupur, and Neelima Sharma. "Harnessing the Power of Natural Products in Drug Discovery." Journal of Pharmaceutical Technology, Research and Management 11, no. 1 (2023): 1–18. http://dx.doi.org/10.15415/jptrm.2023.111001.
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Background: Natural products and their structural analogues have historically played a crucial role in pharmacotherapy, especially in the treatment of cancer and infectious diseases. However, various challenges including screening, isolation, characterization and effectiveness contributed to a decline in natural product research within the pharmaceutical industry. Purpose: This review explores the enduring use of natural compounds in folk medicine with special focus on drug discovery inspired by multifaceted molecular roles of small molecules from natural sources. The article also aims to elucidate how modern modifications of these compounds can lead to the development of innovative molecules with enhanced pharmacological potential & can have good pharmaceutics profile. Methods: To accomplish these objectives, literature has been surveyed from PUBMED, MEDLINE, EMBASE etc. like search engines, for pinpointing detailed technological developments that empower natural product-based drug discovery. Various case studies are incorporated in terms of folklore usage, in process drug discoveries and small molecules scientifically founded with signalling pathway bio stimulation. Conclusions: The journey of natural products from nature to clinic is very complex and time taking. In this pipeline, if attention can be drawn to some major aspects, it will lead to a paradigm shift in drug discovery processes. This can be witnessed by folklore usage of natural products and up laddering multifaceted concepts of small and lead molecules.
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Fakih, Taufik Muhammad, Deis Hikmawati, Endang Sutedja, Reiva Farah Dwiyana, Nur Atik, and Muchtaridi Muchtaridi. "In silico investigation of potential interleukin-8 (IL-8) and Cathelicidin (LL-37) inhibitors for rosacea treatment." Pharmacia 71 (August 14, 2024): 1–12. http://dx.doi.org/10.3897/pharmacia.71.e124099.
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Emerging clinical observations underscore the correlation between interleukin-8 (IL-8) and rosacea. Increased IL-8 expression has been detected in rosacea samples, particularly in moderate to severe manifestations. This phenomenon has prompted the exploration of IL-8 as a prospective therapeutic target for rosacea treatment. To this end, a selection of compounds sourced from the ZINC database, encompassing six small molecules, was made with the intent of identifying promising lead candidates that exhibit drug-like characteristics against IL-8. Through an integrated in silico approach involving structure-guided drug design, encompassing molecular docking, molecular dynamics (MD) simulation, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, protein-peptide docking, and scrutiny of toxicity profiles, it was ascertained that the small molecule ZINC000022339916 effectively inhibits IL-8 activity. These findings present a novel lead compound that warrants further validation through in vitro, in vivo, and ongoing clinical investigations to confirm its potential for therapeutic management of rosacea.
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Fakih, Taufik Muhammad, Deis Hikmawati, Endang Sutedja, Reiva Farah Dwiyana, Nur Atik, and Muchtaridi Muchtaridi. "In silico investigation of potential interleukin-8 (IL-8) and Cathelicidin (LL-37) inhibitors for rosacea treatment." Pharmacia 71 (August 14, 2024): 1–12. https://doi.org/10.3897/pharmacia.71.e124099.
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Emerging clinical observations underscore the correlation between interleukin-8 (IL-8) and rosacea. Increased IL-8 expression has been detected in rosacea samples, particularly in moderate to severe manifestations. This phenomenon has prompted the exploration of IL-8 as a prospective therapeutic target for rosacea treatment. To this end, a selection of compounds sourced from the ZINC database, encompassing six small molecules, was made with the intent of identifying promising lead candidates that exhibit drug-like characteristics against IL-8. Through an integrated in silico approach involving structure-guided drug design, encompassing molecular docking, molecular dynamics (MD) simulation, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, protein-peptide docking, and scrutiny of toxicity profiles, it was ascertained that the small molecule ZINC000022339916 effectively inhibits IL-8 activity. These findings present a novel lead compound that warrants further validation through in vitro, in vivo, and ongoing clinical investigations to confirm its potential for therapeutic management of rosacea.
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Cashman, John R. "Small Molecule Regulation of Stem Cells that Generate Bone, Chondrocyte, and Cardiac Cells." Current Topics in Medicinal Chemistry 20, no. 26 (2020): 2344–61. http://dx.doi.org/10.2174/1568026620666200820143912.
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: Embryonic stem cells (ESCs) are stem cells (SCs) that can self-renew and differentiate into a myriad of cell types. The process of developing stemness is determined by signaling molecules that drive stem cells to a specific lineage. For example, ESCs can differentiate into mature cells (e.g., cardiomyocytes) and mature cardiomyocytes can be characterized for cell beating, action potential, and ion channel function. A goal of this Perspective is to show how small molecules can be used to differentiate ESCs into cardiomyocytes and how this can reveal novel aspects of SC biology. This approach can also lead to the discovery of new molecules of use in cardiovascular disease. : Human induced pluripotent stem cells (hiPSCs) afford the ability to produce unlimited numbers of normal human cells. The creation of patient-specific hiPSCs provides an opportunity to study cell models of human disease. The second goal is to show that small molecules can stimulate hiPSC commitment to cardiomyocytes. How iPSCs can be used in an approach to discover new molecules of use in cardiovascular disease will also be shown in this study. : Adult SCs, including mesenchymal stem cells (MSCs), can likewise participate in self-renewal and multilineage differentiation. MSCs are capable of differentiating into osteoblasts, adipocytes or chondrocytes. A third goal of this Perspective is to describe differentiation of MSCs into chondrogenic and osteogenic lineages. Small molecules can stimulate MSCs to specific cell fate both in vitro and in vivo. In this Perspective, some recent examples of applying small molecules for osteogenic and chondrogenic cell fate determination are summarized. Underlying molecular mechanisms and signaling pathways involved are described. Small molecule-based modulation of stem cells shows insight into cell regulation and potential approaches to therapeutic strategies for MSC-related diseases.
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Velagapudi, Sai Pradeep, Michael D. Cameron, Christopher L. Haga, et al. "Design of a small molecule against an oncogenic noncoding RNA." Proceedings of the National Academy of Sciences 113, no. 21 (2016): 5898–903. http://dx.doi.org/10.1073/pnas.1523975113.
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The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif–small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.
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Shubhangi, H. Bhowate* Dr. Dinesh R. Chaple Dr. Alpana J. asnani Pranita I. Rathod Aishwarya V. Lichade Vaishnavi S. Bhure. "Molecular Docking: A Powerful Tool In Modern Drug Discovery And Its Approaches." International Journal in Pharmaceutical Sciences 1, no. 10 (2023): 170–81. https://doi.org/10.5281/zenodo.10017630.
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The field of computer-aided drug design and discovery (CADD) has been growing rapidly in recent years, with many successes. Both large pharmaceutical companies and academia use CADD for drug lead discovery. Advances in structural informatics, genomics, and proteomics have been vital in modern drug discovery and development. Research over the past two decades has focused on studying different docking algorithms to predict the active site of a molecule. Various docking programs have been developed to visualize the 3D structure of a molecule, and docking scores can be analysed using different computational methods. Molecular Docking is a structure-based virtual screening (SBVS) technique used to position computer-generated three-dimensional structures of small molecules into a target structure in various positions, conformations, and orientations. Protein-ligand docking is a new concept that has various applications and is significant in structure-based drug design (SBDD), Lead Optimization, and Evaluation of Biochemical pathways, as well as in De Novo drug design. This review provides a comprehensive explanation of Molecular Docking and how it helps in the Molecular Recognition Process towards the discovery of new drug leads by estimating the binding mode and affinity of the complex formed.
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Ajay, Amrendra K., Philip Chu, Poojan Patel, et al. "High-Throughput/High Content Imaging Screen Identifies Novel Small Molecule Inhibitors and Immunoproteasomes as Therapeutic Targets for Chordoma." Pharmaceutics 15, no. 4 (2023): 1274. http://dx.doi.org/10.3390/pharmaceutics15041274.
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Chordomas account for approximately 1–4% of all malignant bone tumors and 20% of primary tumors of the spinal column. It is a rare disease, with an incidence estimated to be approximately 1 per 1,000,000 people. The underlying causative mechanism of chordoma is unknown, which makes it challenging to treat. Chordomas have been linked to the T-box transcription factor T (TBXT) gene located on chromosome 6. The TBXT gene encodes a protein transcription factor TBXT, or brachyury homolog. Currently, there is no approved targeted therapy for chordoma. Here, we performed a small molecule screening to identify small chemical molecules and therapeutic targets for treating chordoma. We screened 3730 unique compounds and selected 50 potential hits. The top three hits were Ribociclib, Ingenol-3-angelate, and Duvelisib. Among the top 10 hits, we found a novel class of small molecules, including proteasomal inhibitors, as promising molecules that reduce the proliferation of human chordoma cells. Furthermore, we discovered that proteasomal subunits PSMB5 and PSMB8 are increased in human chordoma cell lines U-CH1 and U-CH2, confirming that the proteasome may serve as a molecular target whose specific inhibition may lead to better therapeutic strategies for chordoma.
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Habchi, Johnny, Sean Chia, Ryan Limbocker та ін. "Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease". Proceedings of the National Academy of Sciences 114, № 2 (2016): E200—E208. http://dx.doi.org/10.1073/pnas.1615613114.
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The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer’s disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.
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Anxolabéhère-Mallart, Elodie, Julien Bonin, Claire Fave, and Marc Robert. "Small-molecule activation with iron porphyrins using electrons, photons and protons: some recent advances and future strategies." Dalton Transactions 48, no. 18 (2019): 5869–78. http://dx.doi.org/10.1039/c9dt00136k.
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Substituted tetraphenyl Fe porphyrins are versatile molecular catalysts for the activation of small molecules (such as O<sub>2</sub>, H<sup>+</sup> or CO<sub>2</sub>), which could lead to renewable energy storage, the direct production of fuels or new catalytic relevant processes.
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Alberti, S., and S. Parodi. "Signaling Protein Networks as Targets of New Antineoplastic Drugs." International Journal of Biological Markers 18, no. 1 (2003): 57–61. http://dx.doi.org/10.1177/172460080301800110.
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In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from “-omic” approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, “intelligent” drug candidates. An additional medicinal chemistry strategy (via 40–50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery.
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Bozhko, Y. Y., R. K. Zhdanov, K. V. Getz, and V. R. Belosludov. "Effect of the THF molecules on the hydrate cavities formation with adding NaCL molecules into the modeling system." Journal of Physics: Conference Series 2057, no. 1 (2021): 012077. http://dx.doi.org/10.1088/1742-6596/2057/1/012077.
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Abstract In this work, using molecular dynamics methods by Gromacs package we simulate the hydrate formation in systems containing THF, water, and NACL molecules at different thermodynamic conditions and concentration of THF molecules. The curves of the number of hydrogen bonds are obtained depending on the simulation time at different temperatures. The computer simulations results show that the hydrogen bonds between THF and water molecules are relatively weak, with a maximum number of two water molecules hydrogen bonded to THF, but THF can facilitate water molecules rearrangement to form a pentagonal or hexagonal planar ring that is the part of clathrate cavity. In addition, the THF molecule can significantly increase the likelihood to form clathrate cavities suitable for the second guest molecule. The effect of THF molecules concentration on the hydrate cavities formation with adding NaCL molecules into the modeling system is shown. In this work, data are obtained on the magnitude of torsion angles, the percentage of which increases depending on the simulation time, which allows concluding that labile large and small cavities of sII hydrates are formed. The increase in the THF molecules concentration is shown to lead to a decrease in the hydrogen bonds number of water molecules in the simulated system.
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Rahman, Sadia, Karlo Wittine, Mirela Sedić, and Elitza P. Markova-Car. "Small Molecules Targeting Biological Clock; A Novel Prospective for Anti-Cancer Drugs." Molecules 25, no. 21 (2020): 4937. http://dx.doi.org/10.3390/molecules25214937.
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The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer.
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Smith, Stephen, Claudia Cianci, and Ramon Grima. "Macromolecular crowding directs the motion of small molecules inside cells." Journal of The Royal Society Interface 14, no. 131 (2017): 20170047. http://dx.doi.org/10.1098/rsif.2017.0047.
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It is now well established that cell interiors are significantly crowded by macromolecules, which impede diffusion and enhance binding rates. However, it is not fully appreciated that levels of crowding are heterogeneous, and can vary substantially between subcellular regions. In this article, starting from a microscopic model, we derive coupled nonlinear partial differential equations for the concentrations of two populations of large and small spherical particles with steric volume exclusion. By performing an expansion in the ratio of the particle sizes, we find that the diffusion of a small particle in the presence of large particles obeys an advection–diffusion equation, with a reduced diffusion coefficient and a velocity directed towards less crowded regions. The interplay between advection and diffusion leads to behaviour that differs significantly from Brownian diffusion. We show that biologically plausible distributions of macromolecules can lead to highly non-Gaussian probability densities for the small particle position, including asymmetrical and multimodal densities. We confirm all our results using hard-sphere Brownian dynamics simulations.
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Lin, Tongxiang, and Shouhai Wu. "Reprogramming with Small Molecules instead of Exogenous Transcription Factors." Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/794632.
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Induced pluripotent stem cells (iPSCs) could be employed in the creation of patient-specific stem cells, which could subsequently be used in various basic and clinical applications. However, current iPSC methodologies present significant hidden risks with respect to genetic mutations and abnormal expression which are a barrier in realizing the full potential of iPSCs. A chemical approach is thought to be a promising strategy for safety and efficiency of iPSC generation. Many small molecules have been identified that can be used in place of exogenous transcription factors and significantly improve iPSC reprogramming efficiency and quality. Recent studies have shown that the use of small molecules results in the generation of chemically induced pluripotent stem cells from mouse embryonic fibroblast cells. These studies might lead to new areas of stem cell research and medical applications, not only human iPSC by chemicals alone, but also safe generation of somatic stem cells for cell based clinical trials and other researches. In this paper, we have reviewed the recent advances in small molecule approaches for the generation of iPSCs.
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Solomon, Gemma C., Justin P. Bergfield, Charles A. Stafford, and Mark A. Ratner. "When “small” terms matter: Coupled interference features in the transport properties of cross-conjugated molecules." Beilstein Journal of Nanotechnology 2 (December 29, 2011): 862–71. http://dx.doi.org/10.3762/bjnano.2.95.
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Quantum interference effects offer opportunities to tune the electronic and thermoelectric response of a quantum-scale device over orders of magnitude. Here we focus on single-molecule devices, in which interference features may be strongly affected by both chemical and electronic modifications to the system. Although not always desirable, such a susceptibility offers insight into the importance of “small” terms, such as through-space coupling and many-body charge–charge correlations. Here we investigate the effect of these small terms using different Hamiltonian models with Hückel, gDFTB and many-body theory to calculate the transport through several single-molecule junctions, finding that terms that are generally thought to only slightly perturb the transport instead produce significant qualitative changes in the transport properties. In particular, we show that coupling of multiple interference features in cross-conjugated molecules by through-space coupling will lead to splitting of the features, as can correlation effects. The degeneracy of multiple interference features in cross-conjugated molecules appears to be significantly more sensitive to perturbations than those observed in equivalent cyclic systems and this needs to be considered if such supernodes are required for molecular thermoelectric devices.
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Alshiraihi, Ilham M., Dillon K. Jarrell, Zeyad Arhouma, et al. "In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells." International Journal of Molecular Sciences 21, no. 24 (2020): 9549. http://dx.doi.org/10.3390/ijms21249549.
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SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.
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Ma, Li, Haiyan Gong, Haiyan Zhu та ін. "Identification Of a Novel Small-Molecule TNFα Inhibitor With Activity Against Inflammation In a Hepatitis Mouse Model". Blood 122, № 21 (2013): 4229. http://dx.doi.org/10.1182/blood.v122.21.4229.4229.
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Abstract Over-expression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To date, significant advances have been made in the development of biological agents targeting TNFα and its signaling components. There are several well known commercial TNFα inhibitors, such as infliximab, adalimumab and etanercept, all of which are TNFα antibodies or TNFR1-Fc chimeras and function to prevent TNFα from binding to its receptor. Those biomacromolecular agents have been proved to be effective in the treatment of inflammatory bowel disease and rheumatoid arthritis due to their unique superiorities such as high specificity. However, several severe limitations such as poor stability, cost-ineffective commercial-scale production and exclusion from blood/brain barrier have also emerged. Instead, small-molecule chemical compounds have been appreciated as appropriate alternatives for overcoming most disadvantages associated with macromolecular inhibitors. Furthermore, they offer additional clinical benefits such as simpler preparation for oral medicine. Now by the use of computer-aided drug design (CADD) and cell-based assays in vitro, several selective small-molecule antagonists of TNFα activity have been identified. They include broad-spectrum inhibitors targeting the key molecules of the intracellular TNFα pathway, functionally uncharacterized inhibitors of TNFα expression, inhibitors of the processing enzyme TNFα converting enzyme (TACE), and molecules that directly bind to TNFR or prevent TNFα-TNFR interactions. Although the small-molecule inhibitors are capable of blocking the biological activity of TNFα in vitro, few have been shown to abrogate or reduce TNFα-induced inflammatory responses in vivo and exhibit high IC50 and severe side effects. Also, none of the small-molecular inhibitors have been reported to successfully block TNFα’s interaction with TNFR through direct binding to TNFα. Thus, development of small molecules for TNFα therapy remains a major challenge. In this study, to explore chemical inhibitors against TNFα activity, we applied CADD combined with in vitro and cell-based assays and identified a lead chemical compound (named as C87 thereafter) from a compound library including about 90,000 small molecular compounds, which directly binds to TNFα indicated by SPR assay, and it potently inhibits TNFα-induced cytotoxicity (IC50=8.73μM) and effectively blocks TNFα–triggered signaling activities. More importantly, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα mediated inflammatory diseases. Disclosures: No relevant conflicts of interest to declare.
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Jamtsho, Tenzin, Karma Yeshi, Matthew J. Perry, Alex Loukas, and Phurpa Wangchuk. "Approaches, Strategies and Procedures for Identifying Anti-Inflammatory Drug Lead Molecules from Natural Products." Pharmaceuticals 17, no. 3 (2024): 283. http://dx.doi.org/10.3390/ph17030283.
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Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.
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Gong, Chang, Zihao Liu, Qun Lin, et al. "Anti-PITPNM3 small molecular compounds reverse breast cancer metastasis by targeting PITPNM3." Journal of Clinical Oncology 39, no. 15_suppl (2021): e15005-e15005. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15005.
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e15005 Background: Recent studies highlight the fundamental roles of PITPNM3 in breast cancer metastasis. PITPNM3 is identified as the functional receptor of CCL18 and promotes breast cancer cell invasion and metastasis by binding with CCL18. Since anti-CCL18 neutralized antibodies shows medium binding affinity which restricts their clinical application, small molecular inhibitors targeting PITPNM3 are needed to be further investigated. Therefore, we identified several first in class small molecular inhibitors potentially targeting PITPNM3 and can inhibit breast cancer metastasis conducted by PITPNM3 activation. Methods: We performed computer-assisted drug design by constructing PITPNM3 homology model, characterizing potential binding pockets and docking preselected high diversity structured small molecule compounds into the static PITPNM3 model. Top 100 small molecules in silico scores were selected and screened through basic experiments. After screening, the anti-metastasis effects of selected compounds were tested through transwell migration and invasion assay. Immunofluorescence and qPCR were applied to confirm the expression of vimentin and CDH1. Western blot were used to clarify the inhibition effects of selected compounds on PITPNM3 signaling pathways. Results: By using homology remodeling, we successfully constructed the PITPNM3(680-920aa) protein model. The PITPNM3(680-920aa) domain is responsible for interacting with PYK2 and phosphorylating PYK2. The phosphorylation of PYK2 conducted by PITPNM3 signaling pathway will lead to metastasis and epithelial-mesenchymal transition (EMT) of breast cancer cells. We then characterized the potential binding pockets of this static model and a druggable site was founded. More than 50K molecules with high diversity were docked into this druggable site and scored through their docking performance. Finally, top 100 scored small molecules were selected. In addition, through 1 rounds of toxicity screening, 1 round of transwell migration assay screening and 1 round of transwell invasion assay screening, 4 small molecules with higher bioactivity is identified and 1 compound with the highest bioactivity as well as docking performance among 50K small molecules is chose. This compound can inhibit CCL18 treatment as well as tumor associated macrophage co-culture mediated migration and invasion. Besides, it can also inhibit the phophorylation of PYK2 and Src without inhibition the expression of PITPNM3. Conclusions: Our findings identify the first-in-class anti-PITPNM3 small molecule inhibitors. These compounds can inhibit PITPNM3 signaling pathway and reverse breast cancer metastasis.
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Heller, Markus, and Horst Kessler. "NMR spectroscopy in drug design." Pure and Applied Chemistry 73, no. 9 (2001): 1429–36. http://dx.doi.org/10.1351/pac200173091429.
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The process of preclinical drug discovery consists of two steps: finding of initial hits (binding ligands to a medicinal relevant target, usually a protein) and lead optimization. Nuclear magnetic resonance spectroscopy is a powerful tool that can provide valuable information to every step of drug development. NMR is commonly used for characterizing the structure and molecular dynamics of target or ligand molecules. During the structure-based lead optimization, NMR provides insight into the structural and dynamical properties of the target-ligand complex. Recently, the use of NMR in the lead finding process by screening technologies has been shown. For the latter use, new techniques have also been developed. Those techniques, in combination with high throughput, have lead to an efficient screening of libraries composed of small molecules. In this article, the role of NMR during the discovery of a drug candidate is described.
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Nödling, Alexander R., Emily M. Mills, Xuefei Li, et al. "Cyanine dye mediated mitochondrial targeting enhances the anti-cancer activity of small-molecule cargoes." Chemical Communications 56, no. 34 (2020): 4672–75. http://dx.doi.org/10.1039/c9cc07931a.
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Wan, Jing, Yang Li, Jared Benson, et al. "Dynamic processes in transient phases during self-assembly of organic semiconductor thin films." Molecular Systems Design & Engineering 7, no. 1 (2022): 34–43. http://dx.doi.org/10.1039/d1me00078k.
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Crystallization of organic semiconductor small molecules from solution proceeds in multiple steps. This study describes how asymmetric molecules lead to long-lived transient phases and their impact on carrier mobility for electronic devices.
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Sun, Saisai, Jianyi Yang, and Zhaolei Zhang. "RNALigands: a database and web server for RNA–ligand interactions." RNA 28, no. 2 (2021): 115–22. http://dx.doi.org/10.1261/rna.078889.121.
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RNA molecules can fold into complex and stable 3D structures, allowing them to carry out important genetic, structural, and regulatory roles inside the cell. These complex structures often contain 3D pockets made up of secondary structural motifs that can be potentially targeted by small molecule ligands. Indeed, many RNA structures in PDB contain bound small molecules, and high-throughput experimental studies have generated a large number of interacting RNA and ligand pairs. There is considerable interest in developing small molecule lead compounds targeting viral RNAs or those RNAs implicated in neurological diseases or cancer. We hypothesize that RNAs that have similar secondary structural motifs may bind to similar small molecule ligands. Toward this goal, we established a database collecting RNA secondary structural motifs and bound small molecule ligands. We further developed a computational pipeline, which takes as input an RNA sequence, predicts its secondary structure, extracts structural motifs, and searches the database for similar secondary structure motifs and interacting small molecule. We demonstrated the utility of the server by querying α-synuclein mRNA 5′ UTR sequence and finding potential matches which were validated as correct. The server is publicly available at http://RNALigands.ccbr.utoronto.ca. The source code can also be downloaded at https://github.com/SaisaiSun/RNALigands.
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Rivera-Vélez, Sol-Maiam, and Nicolas F. Villarino. "Feline urine metabolomic signature: characterization of low-molecular-weight substances in urine from domestic cats." Journal of Feline Medicine and Surgery 20, no. 2 (2017): 155–63. http://dx.doi.org/10.1177/1098612x17701010.
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Objectives This aim of this study was to characterize the composition and content of the feline urine metabolome. Methods Eight healthy domestic cats were acclimated at least 10 days before starting the study. Urine samples (~2 ml) were collected by ultrasound-guided cystocentesis. Samples were centrifuged at 1000 × g for 8 mins, and the supernatant was analyzed by gas chromatography/time-of-flight mass spectrometery. The urine metabolome was characterized using an untargeted metabolomics approach. Results Three hundred and eighteen metabolites were detected in the urine of the eight cats. These molecules are key components of at least 100 metabolic pathways. Feline urine appears to be dominated by carbohydrates, carbohydrate conjugates, organic acid and derivatives, and amino acids and analogs. The five most abundant molecules were phenaceturic acid, hippuric acid, pseudouridine phosphate and 3-(4-hydroxyphenyl) propionic acid. Conclusions and relevance This study is the first to characterize the feline urine metabolome. The results of this study revealed the presence of multiple low-molecular-weight substances that were not known to be present in feline urine. As expected, the origin of the metabolites detected in urine was diverse, including endogenous compounds and molecules biosynthesized by microbes. Also, the diet seemed to have had a relevant role on the urine metabolome. Further exploration of the urine metabolic phenotype will open a window for discovering unknown, or poorly understood, metabolic pathways. In turn, this will advance our understanding of feline biology and lead to new insights in feline physiology, nutrition and medicine.
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Monjas, L., L. J. Y. M. Swier, A. R. de Voogd, R. C. Oudshoorn, A. K. H. Hirsch, and D. J. Slotboom. "Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria." MedChemComm 7, no. 5 (2016): 966–71. http://dx.doi.org/10.1039/c6md00022c.
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This work presents new small molecules that bind to the protein ThiT, which confers substrate specificity to the Energy-Coupling Factor (ECF) transporter for thiamine. Further development of the molecules may lead to compounds with antimicrobial activity.
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Fei, Chengbin, Nengxu Li, Mengru Wang, et al. "Lead-chelating hole-transport layers for efficient and stable perovskite minimodules." Science 380, no. 6647 (2023): 823–29. http://dx.doi.org/10.1126/science.ade9463.
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The defective bottom interfaces of perovskites and hole-transport layers (HTLs) limit the performance of p-i-n structure perovskite solar cells. We report that the addition of lead chelation molecules into HTLs can strongly interact with lead(II) ion (Pb 2+ ), resulting in a reduced amorphous region in perovskites near HTLs and a passivated perovskite bottom surface. The minimodule with an aperture area of 26.9 square centimeters has a power conversion efficiency (PCE) of 21.8% (stabilized at 21.1%) that is certified by the National Renewable Energy Laboratory (NREL), which corresponds to a minimal small-cell efficiency of 24.6% (stabilized 24.1%) throughout the module area. Small-area cells and large-area minimodules with lead chelation molecules in HTLs had a light soaking stability of 3010 and 2130 hours, respectively, at an efficiency loss of 10% from the initial value under 1-sun illumination and open-circuit voltage conditions.
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Soffer, Adam, Samuel Joshua Viswas, Shahar Alon, et al. "MolOptimizer: A Molecular Optimization Toolkit for Fragment-Based Drug Design." Molecules 29, no. 1 (2024): 276. http://dx.doi.org/10.3390/molecules29010276.
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MolOptimizer is a user-friendly computational toolkit designed to streamline the hit-to-lead optimization process in drug discovery. MolOptimizer extracts features and trains machine learning models using a user-provided, labeled, and small-molecule dataset to accurately predict the binding values of new small molecules that share similar scaffolds with the target in focus. Hosted on the Azure web-based server, MolOptimizer emerges as a vital resource, accelerating the discovery and development of novel drug candidates with improved binding properties.
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Liu, Lu, Xi Zhao, and Xuri Huang. "Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder–Decoder Model." International Journal of Molecular Sciences 25, no. 4 (2024): 2357. http://dx.doi.org/10.3390/ijms25042357.
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The receptor tyrosine kinase RET (rearranged during transfection) plays a vital role in various cell signaling pathways and is a critical factor in the development of the nervous system. Abnormal activation of the RET kinase can lead to several cancers, including thyroid cancer and non-small-cell lung cancer. However, most RET kinase inhibitors are multi-kinase inhibitors. Therefore, the development of an effective RET-specific inhibitor continues to present a significant challenge. To address this issue, we built a molecular generation model based on fragment-based drug design (FBDD) and a long short-term memory (LSTM) encoder–decoder structure to generate receptor-specific molecules with novel scaffolds. Remarkably, our model was trained with a molecular assembly accuracy of 98.4%. Leveraging the pre-trained model, we rapidly generated a RET-specific-candidate active-molecule library by transfer learning. Virtual screening based on our molecular generation model was performed, combined with molecular dynamics simulation and binding energy calculation, to discover specific RET inhibitors, and five novel molecules were selected. Further analyses indicated that two of these molecules have good binding affinities and synthesizability, exhibiting high selectivity. Overall, this investigation demonstrates the capacity of our model to generate novel receptor-specific molecules and provides a rapid method to discover potential drugs.
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Parate, Shraddha, Vikas Kumar, Danishuddin, Jong Hong, and Keun Lee. "Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics." International Journal of Molecular Sciences 22, no. 10 (2021): 5311. http://dx.doi.org/10.3390/ijms22105311.
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Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.
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Bergfield, Justin P., Joshua D. Barr, and Charles A. Stafford. "Transmission eigenvalue distributions in highly conductive molecular junctions." Beilstein Journal of Nanotechnology 3 (January 16, 2012): 40–51. http://dx.doi.org/10.3762/bjnano.3.5.
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Background: The transport through a quantum-scale device may be uniquely characterized by its transmission eigenvalues τ n . Recently, highly conductive single-molecule junctions (SMJ) with multiple transport channels (i.e., several τ n > 0) have been formed from benzene molecules between Pt electrodes. Transport through these multichannel SMJs is a probe of both the bonding properties at the lead–molecule interface and of the molecular symmetry. Results: We use a many-body theory that properly describes the complementary wave–particle nature of the electron to investigate transport in an ensemble of Pt–benzene–Pt junctions. We utilize an effective-field theory of interacting π-electrons to accurately model the electrostatic influence of the leads, and we develop an ab initio tunneling model to describe the details of the lead–molecule bonding over an ensemble of junction geometries. We also develop a simple decomposition of transmission eigenchannels into molecular resonances based on the isolated resonance approximation, which helps to illustrate the workings of our many-body theory, and facilitates unambiguous interpretation of transmission spectra. Conclusion: We confirm that Pt–benzene–Pt junctions have two dominant transmission channels, with only a small contribution from a third channel with τ n << 1. In addition, we demonstrate that the isolated resonance approximation is extremely accurate and determine that transport occurs predominantly via the HOMO orbital in Pt–benzene–Pt junctions. Finally, we show that the transport occurs in a lead–molecule coupling regime where the charge carriers are both particle-like and wave-like simultaneously, requiring a many-body description.
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Dheeraj, Arpit, Dhanir Tailor, Angel Resendez, et al. "Abstract 3997: Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer." Cancer Research 82, no. 12_Supplement (2022): 3997. http://dx.doi.org/10.1158/1538-7445.am2022-3997.
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Abstract Aberration in the protein translation can lead to changes in the protein expression that can serve as the drivers of tumor progression. Ribosomes are a molecular machine that acts as a hub for protein synthesis, and dysregulation of ribosome function is causative for cancer formation. Our investigation on the causes of breast cancer progression has identified a small molecule ‘SU056’ that shows efficacy against TNBC models. SU056 treatment inhibits growth and clonogenic potential of TNBC cells (MDA-MB-231, MDA-MB-468, SUM159, 4T1, EMT6 and E0771), by arresting the cell cycle progression through G2/M phase. Proteomics analysis suggested translational process as a target of SU056 in these cells. We found that its treatment modulated expression of several molecules of translational complex such as RPL (RPL9, RPL11, RPL15), RPS (RPSA, RPS9, RPS16, RPS20), and translation initiation factors (eIF6, eIF5, eIF4A, eIF4G), which leads to overall inhibition. This was further confirmed by tumor xenograft study with different TNBC models, which also showed that metastatic nodules in the lungs were inhibited by SU056 compared to control group. The results were further confirmed in a Patient Derived Xenograft (PDX) model SUTI151. Overall, our study has identified a lead candidate SU056, and provides strong foundation to further develop a new therapy for treatment of patients with TNBCs. Citation Format: Arpit Dheeraj, Dhanir Tailor, Angel Resendez, Fernando Jose Marques, Abel Bermudez, Sharon Pitteri, Sanjay Malhotra. Inhibiting ribosomal proteins with a small molecule: Therapeutic strategy for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3997.
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Ivancevic, Marko R., Jesse A. Wisch, Quinn C. Burlingame, Barry P. Rand, and Yueh-Lin Loo. "(Invited) A General Approach to Induce Ultralong Room Temperature Phosphorescence in Organic Small Molecules." ECS Meeting Abstracts MA2024-01, no. 31 (2024): 1524. http://dx.doi.org/10.1149/ma2024-01311524mtgabs.
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Interest in organic small molecules that exhibit second-scale phosphorescence at room temperature has grown immensely in recent years due to their potential applications in sensing, anticounterfeiting, and bioimaging. However, such material systems are rare—requiring second-scale triplet lifetimes, efficient intersystem crossing, and slow rates of nonradiative recombination. This third requirement has been met by isolating phosphors in a rigid matrix, or by aggregating them into densely packed crystals or powders to suppress the molecular vibrations that lead to recombination. While these techniques work well for a small subset of molecules with specific properties, most isolated molecules in a rigid matrix do not phosphoresce, and most macroscopic aggregates experience significant triplet quenching. In this work, we find a middle ground between these extremes by forming microscopic [approximately submicron sized] phosphor aggregates in rigid polymer matrices using a simple drop casting and thermal annealing process. Using this technique, we activate second-scale phosphorescence at room temperature in 20 molecules that do not otherwise phosphoresce using conventional matrix-isolation or crystallization approaches. We find that increased chromophore loading increases aggregate sizes. Excitons are thus able to diffuse further and interact more, and triplet-triplet annihilation dominates. Furthermore, we determine that excimer formation in some aggregates leads to increased rates of triplet generation—complementing the effect of nonradiative recombination suppression and further enhancing phosphorescence. In sum, the simplicity and robustness of this blending approach significantly loosens the design constraints to access second-scale emission with organic phosphors, allowing researchers to choose from a broader catalog of organic materials to match the desired properties for a given application.
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Taylor, Howard M. "A Model for the Failure Process of Semicrystalline Polymer Materials under Static Fatigue." Probability in the Engineering and Informational Sciences 1, no. 2 (1987): 133–62. http://dx.doi.org/10.1017/s026996480000036x.
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A semicrystalline polymer fiber is a composite material consisting of difficult-to-deform crystals joined by more easily deformed and more easily broken amorphous materials. The failure process begins at the atomic level in the amorphous regions where random thermal fluctuations cause, at some time, a molecule to slip relative to other molecules or to rupture at one of its atomic bonds. The frequency of such random events is greatly enhanced by small increases in stress. As molecules slip or rupture, neighboring molecules become overloaded, thus increasing their failure rates. Such molecule failures accumulate locally and give rise to growing microcracks, although the exact kinetic mechanisms are not well understood. These growing minute cracks are the irreversible changes in the microstructure of the material that ultimately lead to macroscopic failure of the fiber.
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Pattabhi, Sowmya, Courtney R. Wilkins, Ran Dong, et al. "Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway." Journal of Virology 90, no. 5 (2015): 2372–87. http://dx.doi.org/10.1128/jvi.02202-15.
Full textAbstract:
ABSTRACTThe cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays a critical role in antiviral immunity to drive the expression of innate immune response genes, including those encoding antiviral factors, type 1 interferon, and immune modulatory cytokines, that act in concert to restrict virus replication. Thus, small molecule agonists that can promote IRF3 activation and induce innate immune gene expression could serve as antivirals to induce tissue-wide innate immunity for effective control of virus infection. We identified small molecule compounds that activate IRF3 to differentially induce discrete subsets of antiviral genes. We tested a lead compound and derivatives for the ability to suppress infections caused by a broad range of RNA viruses. Compound administration significantly decreased the viral RNA load in cultured cells that were infected with viruses of the familyFlaviviridae, including West Nile virus, dengue virus, and hepatitis C virus, as well as viruses of the familiesFiloviridae(Ebola virus),Orthomyxoviridae(influenza A virus),Arenaviridae(Lassa virus), andParamyxoviridae(respiratory syncytial virus, Nipah virus) to suppress infectious virus production. Knockdown studies mapped this response to the RIG-I-like receptor pathway. This work identifies a novel class of host-directed immune modulatory molecules that activate IRF3 to promote host antiviral responses to broadly suppress infections caused by RNA viruses of distinct genera.IMPORTANCEIncidences of emerging and reemerging RNA viruses highlight a desperate need for broad-spectrum antiviral agents that can effectively control infections caused by viruses of distinct genera. We identified small molecule compounds that can selectively activate IRF3 for the purpose of identifying drug-like molecules that can be developed for the treatment of viral infections. Here, we report the discovery of a hydroxyquinoline family of small molecules that can activate IRF3 to promote cellular antiviral responses. These molecules can prophylactically or therapeutically control infection in cell culture by pathogenic RNA viruses, including West Nile virus, dengue virus, hepatitis C virus, influenza A virus, respiratory syncytial virus, Nipah virus, Lassa virus, and Ebola virus. Our study thus identifies a class of small molecules with a novel mechanism to enhance host immune responses for antiviral activity against a variety of RNA viruses that pose a significant health care burden and/or that are known to cause infections with high case fatality rates.