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

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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).