Virtual Winter School on Computational Chemistry
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Dr. Robert J. Doerksen
Associate Dean, Graduate School Associate Professor of Medicinal Chemistry, Department of BioMolecular Sciences Research Associate Professor, Research Institute of Pharmaceutical Sciences University of Mississippi, University, MS, USA
A wide variety of computational chemistry methods are useful in the search for new drugs. These approaches are collectively termed computational medicinal chemistry. A typical small molecule drug (molecular weight < 500 Da) needs to interact with or react with a protein target to achieve its useful pharmacological effect. Its path through the human body can also include changing protonation state, crossing lipid barriers, being carried by proteins, and undergoing metabolic transformations. A series of computational methods can be used to study the progress of a drug through the body in the various stages of pharmacokinetics and pharmacodynamics. Three-dimensional representations of both the drug and of what it interacts with are often helpful. For this, conformational search and methods to calculate and rank the relative energies of conformations are necessary. Many electronic structure properties of the drug molecule can be calculated, which can be used to characterize the molecule and predict its behavior. Protein modeling is also important to carry out, including effective use of experimental structural information. The conformations of drug and target can then be used in molecular docking which in turn can serve as a key step in virtual screening to find, from a database of known structures, drug hits with never-before-reported useful pharmacological activity at targets of interest. This presentation will include examples of best-practice application of these methods, such as for identifying selective protein kinase inhibitors or cannabinoid receptor ligands.
ChemAxon Kft. Záhony str. 7., Budapest, Hungary, H-1031
Discovery of a novel drug is an optimizing challenge against an array of chemical and biological attributes to reach the desired efficacy and safety profile. The immense complexity of the human body combined and the astronomically large druggable chemical space hinders the selection of molecules with such a balanced profile. Therefore, the medicinal chemistry toolbox embraces all computational techniques with predictive power to focus the chemical space to the most promising candidates for synthesis and testing. The diversity includes data analysis tools, physics-based simulations, biological target structure driven or ligand structure based approaches [1-3]. While the size of the compound collections vary from a couple of close analogues up to billions of virtual compounds to process. This presentation will highlight general concepts and techniques applied in computer aided drug design, focusing on data and ligand based computational chemistry approaches and showcase solutions developed by ChemAxon.
 Gisbert Schneider, David E Clark, Angew Chem Int Ed Engl. 2019, 5;58(32):10792-10803.
 John G Cumming, Andrew M Davis, Sorel Muresan, Markus Haeberlein, Hongming Chen, Nat Rev Drug Discov,2013, 12(12):948-62.
 Yu-Chen Lo, Stefano E Rensi, Wen Torng, Russ B Altman, Drug Discov Today 2018, 23(8):1538-1546
 Torsten Hoffmanm, Marcus Gastreich, Drug Discov Today, 2019, 24(5):1148-1156.
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