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 subset of the protein surrounding the binding pocket region. Results from the minimizations of solvated complexes of 2‐cyclopropyl‐4‐methyl‐5,11‐dihydro‐5H‐dipyrido[3,2‐b :2′,3′‐e][1,4]diazepin‐6‐one (nevirapine), α‐anilino‐2, 6‐dibromophenylacetamide (α‐APA), and 8‐chloro‐tetrahydro‐imidazo(4,5,1‐jk)(1,4)‐benzodiazepin‐2(1H)‐thione (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as π‐electron donors to aromatic side‐chain residues surrounding the pocket. However, side‐chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed 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 binding energies correlate with EC₅₀ values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. Interactions of the inhibitors with individual residues correlate with crystallographic and site‐specific mutational data. π‐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 formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV‐1 RT that are resistant to the currently available drugs.