title: Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods.
abstract: Computational methods for docking small molecules to proteins are prominent in drug discovery. There are hundreds, if not thousands, of documented examples-and several pertinent cases within our research program. Fifteen years ago, our first docking-guided drug design project yielded nanomolar metalloproteinase inhibitors and illustrated the potential of structure-based drug design. Subsequent applications of docking programs to the design of integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA demonstrated that available docking programs needed significant improvement. At that time, docking programs primarily considered flexible ligands and rigid proteins. We demonstrated that accounting for protein flexibility, employing displaceable water molecules, and using ligand-based pharmacophores improved the docking accuracy of existing methods-enabling the design of bioactive molecules. The success prompted the development of our own program, Fitted, implementing all of these aspects. The primary motivation has always been to respond to the needs of drug design studies; the majority of the concepts behind the evolution of Fitted are rooted in medicinal chemistry projects and collaborations. Several examples follow: (1) Searching for HDAC inhibitors led us to develop methods considering drug-zinc coordination and its effect on the pKa of surrounding residues. (2) Targeting covalent prolyl oligopeptidase (POP) inhibitors prompted an update to Fitted to identify reactive groups and form bonds with a given residue (e.g., a catalytic residue) when the geometry allows it. Fitted-the first fully automated covalent docking program-was successfully applied to the discovery of four new classes of covalent POP inhibitors. As a result, efficient stereoselective syntheses of a few screening hits were prioritized rather than synthesizing large chemical libraries-yielding nanomolar inhibitors. (3) In order to study the metabolism of POP inhibitors by cytochrome P450 enzymes (CYPs)-for toxicology studies-the program Impacts was derived from Fitted and helped us to reveal a complex metabolism with unforeseen stereocenter isomerizations. These efforts, combined with those of other docking software developers, have strengthened our understanding of the complex drug-protein binding process while providing the medicinal chemistry community with useful tools that have led to drug discoveries. In this Account, we describe our contributions over the past 15 years-within their historical context-to the design of drug candidates, including BACE-1 inhibitors, POP covalent inhibitors, G-quadruplex binders, and aminoglycosides binding to nucleic acids. We also remark the necessary developments of docking programs, specifically Fitted, that enabled structure-based design to flourish and yielded multiple fruitful, rational medicinal chemistry campaigns.
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec, Canada H3A 0B8.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec, Canada H3A 0B8.
authors.forename: Joshua
authors.initials: J
authors.lastname: Pottel
authors.affiliation: Molecular Forecaster Inc. , 969 Marc-Aurèle-Fortin, Laval, Québec, Canada H7L 6H9.
authors.forename: Eric
authors.initials: E
authors.lastname: Therrien
authors.affiliation: Royal HaskoningDHV , Laan 1914 35, 3818 EX Amersfoort, The Netherlands.
authors.forename: Pablo
authors.initials: P
authors.lastname: Englebienne
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec, Canada H3A 0B8.
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec, Canada H3A 0B8.
authors.forename: Anna
authors.initials: A
authors.lastname: Tomberg
authors.affiliation: Human Health Therapeutics, National Research Council Canada , 6100 Royalmount Avenue, Montréal, Québec, Canada H4P 2R2.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Corbeil
mesh_terms: D004247:DNA / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012313:RNA / Q000737:chemistry / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins; D012313:RNA; D004247:DNA