MOLECULAR MODELING STUDIES OF HIV-1 REVERSE-TRANSCRIPTASE NONNUCLEOSIDE INHIBITORS - TOTAL-ENERGY OF COMPLEXATION AS A PREDICTOR OF DRUG PLACEMENT AND ACTIVITY

Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subs et of the protein surrounding the binding pocket region. Results from the minimizations of solvated complexes of ydro-5H-dipyrido[3,2-b:2',3 '-e][1,4]diazepin-6-one (nevirapine), alpha-anilino-2, 6-dibromophenyl acetamide (alpha-APA), and 8-chloro-tetrahydro-imidazo (4,5,1-jk)(1,4) -benzodiazepin-2(1H)-thione (TIBO) show that all three inhibitors main tain a very similar conformational shape, roughly overlay each other i n the binding pocket, and appear to function as pi-electron donors to aromatic side-chain residues surrounding the pocket. However, side-cha in residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waa ls contacts. Consequently, the results from the calculated minimizatio ns reveal that only when the inhibitors are modeled in a site construc ted from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these bin ding energies correlate with EC(50) values determined for all three in hibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug i s endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically mo re stable and the drug less stable in their complexes as compared to t he reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. Interactions of the in hibitors with individual residues correlate with crystallographic and site-specific mutational data. pi-Stacking interactions are important in binding and correlate with drug HOMO RHF/6-31G energies. Modeling results are discussed with respect to the mechanism of complex formati on and the design of nonnucleoside inhibitors that will be more effect ive against mutants of HIV-1 RT that are resistant to the currently av ailable drugs.