The aim of the work is to develop, apply, and disseminate computational technology for the optimization of lead compounds and for the design of new chemical entities that selectively block HIV infection and replication. The advances include development of computational tools (a) to predict protein-ligand binding affinities and the structures of protein-ligand complexes, (b) to evaluate properties and drug-likeness of proposed molecules, and (c) to create and evaluate virtual libraries of potential inhibitors. Applications of the computational methods yield enhanced knowledge of the structural and energetic factors that govern variations in protein-ligand binding affinities and of the origins of differential effects of protein mutations on drug activities. This knowledge provides a basis for the rational design of drugs that remain effective against a broad range of viral mutants. The proposed applications focus on advances for the development of improved non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). GenMol is used to construct individual organic molecules or combinatorial libraries inside a protein's binding site. Development of the necessary scoring functions requires application to multiple series of NNRTIs with wild type (WT) and all principal NNRTI-induced mutants. The added detail from inclusion of the solvent and configurational sampling in Monte Carlo (MC) simulations permits more accurate characterization of variations in activity. Thus, MC/ELR (extended linear response) studies are also performed for series of NNRTIs with WT and mutant RT with the goal of developing a reliable computational screen to evaluate the potential of proposed NNRTIs. At the highest computational level, MC/FEP (free energy perturbation) calculations are being used to elucidate the atomic level origins of the differential effects of pan-class resistance mutations such as K103N and Y188L on the activity of specific drugs including nevirapine, efavirenz, DPC083, and TMC125. Subsequent, analogous studies will be used to design potent inhibitors of HIV viral entry through disruption of assembly of the fusogenic form of the gp41-gp120 complex; the specific target is a hydrophobic pocket that exists in ridges of a coiled coil formed by N-terminal segments of gp41.
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