Nicolas Moitessier
McGill University
Canada
Title: Fitted, an evolving docking programs addressing unmet medicinal chemistry needs
Biography
Biography: Nicolas Moitessier
Abstract
Docking methods have been prominent in the discovery of novel drugs. Over the 15 years ago, we have been developing a docking program which has been modified to address unmet needs in medicinal chemistry. Initially, our applications of docking programs to integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA revealed the limitations of available docking programs, which were essentially docking flexible ligands to rigid proteins. Over the following year, we developed our own program, Fitted, implementing algorithms for protein flexibility, displaceable water molecules, and ligand-based pharmacophore-oriented docking. Other medicinal chemistry projects motivated most of the concepts and implementation within an ever-evolving docking program. We will present examples of medicinal chemistry-driven implementations such as methods considering drug-zinc coordination and its effect on the pKa of surrounding residues, for HDAC inhibitor design, routines to identify reactive groups and form bonds with a given residue to enable the development of covalent prolyl oligopeptidase (POP) inhibitors, methods to compute transition states while docking for studying the metabolism of POP inhibitors by cytochrome P450 enzymes (CYPs) and others.