Computational studies on HIV-1 protease inhibitors: Influence of calculated inhibitor-enzyme binding affinities on the statistical quality of 3D-QSARCoMFA models

A theoretical study was performed on a set of 38 human immunodeficiency typ e 1 (HIV-1) protease inhibitors that are structurally similar to the AIDS d rug Indinavir. Comparison between the computed binding energies and experim ental activity data (pIC(50)) found a high degree of correlation (r(2) = 0. 82). Three-dimensional quantitative structure-activity relationship (3D-QSA R) models using comparative molecular field analysis (CoMFA) yielded predic ted activities that were in excellent agreement with the corresponding expe rimentally determined values. Inclusion of the calculated enzyme-inhibitor binding energy as an additional descriptor in the CoMFA model yielded a sig nificant improvement in the internal predictive ability of our model (q(2) = 0.45 to q(2) = 0.69). Separate CoMFA models were constructed to evaluate the influence of different alignment schemes (Atom Fit and Field Fit) and d ifferent partial atomic charge assignment schemes (Discover CVFF, Gasteiger -Marsili, and AM1-ESP) on the statistical quality of the models.