Comparative molecular field analysis (CoMFA) and docking studies of non-nucleoside HIV-1 RT inhibitors (NNIs)

A set of TIBO derivatives endowed with reverse transcriptase (RT) inhibitor y activity were analyzed by comparative molecular field analysis (CoMFA). B esides conventional steric and electrostatic fields, molecular lipophilicit y potential (MLP) was also used as a third field in CoMFA. An informative a nd statistically significant model (q(2) = 0.70, r(2) = 0.90, s = 0.46) was obtained by taking into account the three field types together. The key mo lecular determinants governing the RT inhibition by TIBO congeners were det ected at the 3-D level by a careful analysis of the CoMFA isocontour maps. To challenge the predictive ability of the CoMFA model, an external set of thiazolobenzimidazole (TBZ) derivatives were examined. Good predictions, su ggesting a similar binding mode for TIBO and TBZ derivatives, emerged. Flex ible docking experiments on TBZ, TIBO and other NNIs confirmed common bindi ng characteristics, as found out also by CoMFA, and moreover a good correla tion between calculated binding energies and inhibitory potency was found. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.