Comparative molecular field analysis (CoMFA) of a series of symmetrical bis-benzamide cyclic urea derivatives as HIV-1 protease inhibitors.
A 3D-QSAR study using CoMFA methodology was conducted on a series of 29 symmetrical bis-benzamide cyclic urea derivatives having anti-HIV-1-protease activities. Active site minimization of the ligands was used to exclude conformations which are not sterically accessible within the active site. A significant cross validated correlation coefficient q2 (0.724) was obtained indicating the predictive potential of the model for untested compounds of this class. A significant non-cross-validated correlation coefficient (r2) of 0.971 with a low standard error estimate (S) of 0.119 was obtained indicating that the model reliably predicted the ant-protease activities of poorly to highly active compounds. The model was used to predict the anti-protease activities of eight test-set compounds, and the predicted values were in good agreement with the experimental values. The CoMFA coefficient contour plots identified several key features which explain the wide range of activities. The already reported 2D-QSAR along with the CoMFA model presented here may help in designing effective HIV-1 protease inhibitors.
Biochemical Virology Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York 10021, USA.
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D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D014508:Urea