Estimation of binding affinities for HEPT and nevirapine analogues with HTV-1 reverse transcriptase via Monte Carlo simulations

The interactions and energetics associated with the binding of 20 HEPT and 20 nevirapine nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) have been explored in an effort to establish simulation protocols and metho ds that can be used in the development of more effective anti-HIV drugs. Us ing crystallographic structures as starting points, all 40 inhibitors were modeled in the bound and unbound states via Monte Carlo (MC) statistical me chanics methods. Potentially useful descriptors of binding affinity were co nfigurationally averaged for each inhibitor during the MC simulations, and correlations were sought with reported experimental activities. A viable re gression equation was obtained using only four descriptors to correlate the 40 experimental activities with an r(2) of 0.75 and cross-validated q(2) o f 0.69. The computed activities show a rmsd of 0.94 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. The MC resu lts reveal three physically reasonable parameters that control the binding affinities: (1) loss of hydrogen bonds with the inhibitor is unfavorable, ( 2) burial of hydrophobic surface area is favorable, and (3) a good geometri cal fit without steric clashes is needed for the protein-inhibitor complex. It is gratifying that the corresponding descriptors are statistically the most important quantities for determining the anti-HIVRT activity for the 4 0 compounds. Representative examples are also given in which structural and thermodynamic information from the MC simulations is used to help understa nd binding differences for related compounds. A key pi -type hydrogen bond has been identified between secondary-amide nevirapine analogues and Tyr188 A of HIVRT that explains their otherwise surprising activity and the ineffe ctiveness of nevirapine against the Y188C mutant.