3D-quantitative structure-activity relationships of human immunodeficiency virus type-1 proteinase inhibitors: comparative molecular field analysis of 2-heterosubstituted statine derivatives-implications for the design of novel inhibitors.

A set of 100 novel 2-heterosubstituted statine derivatives inhibiting human immunodeficiency virus type-1 proteinase has been investigated by comparative molecular field analysis. In order to combine the structural information available from X-ray analyses with a predictive quantitative structure-activity relationship (QSAR) model, docking experiments of a prototype compound into the receptor were performed, and the 'active conformation' was determined. The structure of the receptor was taken from the published X-ray analysis of the proteinase with bound MVT-101, the latter compound exhibiting high structural similarity with the inhibitors investigated. The validity of the resulting QSARs was confirmed in four different ways. (1) The common parameters, namely, the cross-validated r2 values obtained by the leave-one-out (LOO) method (r2cv = 0.572-0.593), and (2) the accurate prediction of a test set of 67 compounds (q2 = 0.552-0.569) indicated a high consistency of the models. (3) Repeated analyses with two randomly selected cross-validation groups were performed and the cross-validated r2 values monitored. The resulting average r2 values were of similar magnitudes compared to those obtained by the LOO method. (4) The coefficient fields were compared with the steric and electrostatic properties of the receptor and showed a high level of compatibility. Further analysis of the results led to the design of a novel class of highly active compounds containing an additional linkage between P1' and P3'. The predicted activities of these inhibitors were also in good agreement with the experimentally determined values.