Abstract
TIBO (Tetrahydro‐imidazo[4,5,1‐jk][1,4]‐benzodiazepin‐2‐one) and nevirapine (11‐cyclopropyl‐5,11‐dihydro‐4‐methyl‐6H‐dipyrido[3,2‐b:2′,3′‐e][1,4]diazepin‐6‐one) are models for two classes of nonnucleoside inhibitors of the HIV‐1 virus reverse transcriptase (NNRTI). This work presents the parameterization of compounds belonging to these two classes in the Cornell et al. force field through ab initio and semiempirical methods. The new parameters were used in the conformational analysis for TIBO R82913, TIBO R79882, and nevirapine. Various conformational search protocols were tested and the pseudosystematic method SUMM led to the best results. A better understanding of the distribution of conformers was obtained through clustering techniques in the data reduction stages. It was possible to reproduce various experimental data such as the crystallographic structures of the isolated or reverse transcriptase‐complexed (RT) molecules. The proton–proton coupling constants (\documentclass{article}\pagestyle{empty}\begin{document}$,J^{3}_{\mathrm{HH}}$\end{document}) obtained for TIBO through NMR were also reproduced. Cremer and Pople puckering parameters enabled a precise description of both the conformation of the seven‐membered rings and the relative position of the substituents on them. These parameters also demonstrated the efficiency and precision of the two‐stage clustering method. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1817–1829, 2001