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

✍ Scribed by Nitin S. Sapre; Nilanjana Pancholi; Swagata Gupta; Neelima Sapre

• Book ID: 102304032
• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 216 KB
• Volume: 29
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.20931

✦ Synopsis

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 = 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 = 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 = 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. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008