3D-QSAR and docking studies on the HEPT derivatives of HIV-1 reverse transcriptase.

Three-dimensional Quantitative Structure Activity Relationship (3D-QSAR) has been derived for a set of HEPT derivatives of HIV-1 reverse transcriptase (RT) using Comparative Molecular Field Analysis (CoMFA). The CoMFA models have been developed using two different alignment procedures such as common substructure and bioactive conformation. The CoMFA model I is derived from a common substructure procedure that includes steric and electrostatic fields with the cross-validated q(2) and the non-cross-validated r(2) value of 0.86 and 0.97, respectively. The same for the CoMFA model II that is derived based on the bioactive conformation are 0.19 and 0.77, respectively. It is evident from the results that the common substructure-based alignment model has good statistical significance when compared with that of bioactive conformation for the selected systems in this study. The docking study revealed that the conformational flexibility observed at the R3 position favors different orientations of the substitution at the active site of HIV-1 RT and thereby leads to inconsistency in the CoMFA alignment based on bioactive conformation.