title: Comparative molecular field analysis (CoMFA) and docking studies of non-nucleoside HIV-1 RT inhibitors (NNIs).
abstract: A set of TIBO derivatives endowed with reverse transcriptase (RT) inhibitory activity were analyzed by comparative molecular field analysis (CoMFA). Besides conventional steric and electrostatic fields, molecular lipophilicity potential (MLP) was also used as a third field in CoMFA. An informative and statistically significant model (q2 = 0.70, r2 = 0.90, s = 0.46) was obtained by taking into account the three field types together. The key molecular determinants governing the RT inhibition by TIBO congeners were detected 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, suggesting a similar binding mode for TIBO and TBZ derivatives, emerged. Flexible docking experiments on TBZ, TIBO and other NNIs confirmed common binding characteristics, as found out also by CoMFA, and moreover a good correlation between calculated binding energies and inhibitory potency was found.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: Barreca
authors.forename: A
authors.initials: A
authors.lastname: Carotti
authors.forename: A
authors.initials: A
authors.lastname: Carrieri
authors.forename: A
authors.initials: A
authors.lastname: Chimirri
authors.forename: A M
authors.initials: AM
authors.lastname: Monforte
authors.forename: M P
authors.initials: MP
authors.lastname: Calace
authors.forename: A
authors.initials: A
authors.lastname: Rao
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D001569:Benzodiazepines; C073244:1-(2',6'-difluorophenyl)-1H,3H-thiazolo(3,4-a)benzimidazole; C092133:R 79882; D054303:HIV Reverse Transcriptase