3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors.
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 (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.0 A). The best model ( N = 59), derived from Alignment 1 and PM3 charges, shows q (2) = 0.691, SE cv = 0.475, optimum number of components = 6, r (2) = 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 (r (2) 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.
de Brito
Monique Araújo
MA
Programa de Pos-Graduacao em Quimica Organica, Departamento de Quimica Organica, Laboratorio de Modelagem Molecular (LabMMol), Instituto de Quimica, CCMN, UFRJ, Rio de Janeiro, RJ, Brazil. moniquebrito@yahoo.com.br
Rodrigues
Carlos Rangel
CR
Cirino
José Jair Vianna
JJ
de Alencastro
Ricardo Bicca
RB
Castro
Helena Carla
HC
Albuquerque
Magaly Girão
MG
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001554:Benzene / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D019380:Anti-HIV Agents; D011743:Pyrimidines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D001554:Benzene; C030986:pyrimidine; D010100:Oxygen