title: Optimization and computational evaluation of a series of potential active site inhibitors of the V82F/I84V drug-resistant mutant of HIV-1 protease: an application of the relaxed complex method of structure-based drug design.
abstract: The Relaxed Complex method, an approach to structure-based drug design that incorporates the flexibilities of both the ligand and target protein, was applied to the immunodeficiency virus protease system. The control cases used AutoDock3.0.5 to dock a fully flexible version of the prospective drug JE-2147 (aka SM-319777 or KNI-764) to large ensembles of conformations extracted from conventional, all atom, explicitly solvated molecular dynamic simulations of the wild type, and the V82F/I84V drug-resistant mutant of HIV-1 protease. The best set of run parameters from the control cases produced robust results when used against 2200 different conformations of the wild-type HIV-1 protease or against 2200 conformations of the mutant. The results of the control cases, the published advice from experts, and structural intuition were used to design a new series of 23 potential active site inhibitors. The compounds were evaluated by docking them against 700 different conformations of the V82F/I84V mutant. The results of this first round of lead optimization were quite promising. Approximately one-third of that series performed at least slightly better than the parent compound, and four of those compounds displayed significantly better binding affinities against that drug-resistant mutant (within our computational model).
authors.affiliation: Howard Hughes Medical Institute, Center for Theoretical Biological Physics and Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0365, USA. aperryma@caltech.edu
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Perryman
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Andrew McCammon
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D003198:Computer Simulation; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010654:Phenylbutyrates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; C120671:JE 2147; D010654:Phenylbutyrates; D016333:HIV Protease