title: Computational modeling of tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone derivatives: an atomistic drug design approach using Kier-Hall electrotopological state (E-state) indices.
abstract: Quantitative structure-activity relationships (QSAR), based on E-state indices have been developed for a series of tetrahydroimidazo-[4,5,1-jk]-benzodiazepinone derivatives against HIV-1 reverse transcriptase (HIV-1 RT). Statistical modeling using multiple linear regression technique in predicting the anti-HIV activity yielded a good correlation for the training set (R(2) = 0.913, R(2)(adj) = 0.897, Q(2) = 0.849, MSE = 0.190, F-ratio = 59.97, PRESS = 18.05, SSE = 0.926, and p value = 0.00). Leave-one-out cross-validation also reaffirmed the predictions (R(2) = 0.850, R(2)(adj) = 0.824, Q(2) = 0.849, MSE = 0.328, and PRESS = 18.05). The predictive ability of the training set was also cross-validated by a test set (R(2) = 0.812, R(2)(adj) = 0.799, Q(2) = 0.765, MSE = 0.347, F-ratio = 64.69, PRESS = 7.37, SSE = 0.975, and p value = 0.00), which ascertained a satisfactory quality of fit. The results reflect the substitution pattern and suggest that the presence of a bulky and electropositive group in the five-member ring and electron withdrawing groups in the seven-member ring will have a positive impact on the antiviral activity of the derivatives. Bulky groups in the six-member ring do not show an activity-enhancing impact. Outlier analysis too reconfirms our findings. The E-state descriptors indicate their importance in quantifying the electronic characteristics of a molecule and thus can be used in chemical interpretation of electronic and steric factors affecting the biological activity of compounds.
authors: Department of Applied Chemistry, Shri GS Institute of Technology and Sciences, Indore, MP, India. sukusap@yahoo.com nsapre@sgsits.ac.in
authors: Nitin S
authors: NS
authors: Sapre
authors: Nilanjana
authors: N
authors: Pancholi
authors: Swagata
authors: S
authors: Gupta
authors: Neelima
authors: N
authors: Sapre
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001570:Benzodiazepinones