3D-QSAR CoMFA of a Series of DABO Derivatives as HIV-1 Reverse Transcriptase Non-Nucleoside Inhibitors

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• 作者：Monique Araú ; jo de Brito ; Carlos Rangel Rodrigues ; José ; Jair Vianna Cirino ; Ricardo Bicca de Alencastro ; Helena Carla Castro ; Magaly Girã ; o Albuquerque
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2008
• 出版时间：August 2008
• 年：2008
• 卷：48
• 期：8
• 页码：1706-1715
• 全文大小：261K
• 年卷期：v.48,no.8(August 2008)
• ISSN：1549-960X

文摘

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure−activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp³, +1 charge), cutoffs (30 kcal.mol⁻¹ for both steric and electrostatic fields), and grid distance (2.0 Å). The best model (N = 59), derived from Alignment 1 and PM3 charges, shows q² = 0.691, SE_cv = 0.475, optimum number of components = 6, r² = 0.930, SEE = 0.226, and F-value = 115.544. The steric and electrostatic contributions for the best model were 43.2% and 56.8%, respectively. The external predictive ability (r²_pred = 0.918) of the resultant best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, attention should be taken in order to select a substituent for the 4-oxopyrimidine ring, since, as revealed by the best CoMFA model, there are a steric restriction at the C2-position, a electron-rich group restriction at the C6-position (para-substituent of the 6-benzyl group), and a steric allowed region at the C5-position.