Eigen value analysis of HIV-1 integrase inhibitors.

A three-dimensional quantitative structure activity relationship using the eigen value analysis (EVA) paradigm applied to 41 HIV-1 integrase inhibitors that inhibit integrase mediated cleavage (3'-processing step) and integration (3'-strand transfer step) in vitro was performed. The training set consisted of 35 molecules from five structurally diverse classes: salicylhydrazines, lichen acids, coumarins, quinones, and thiazolothiazepines. Models derived using semiempirical (MOPAC AM1 and PM3) calculated normal-mode frequencies were compared. The predictive ability of each resultant model was evaluated using a test set comprised of six molecules belonging to a different structural class: hydrazides. Models derived using AM1 method showed considerable internal as well as external predictivity (r(2)(cv) = 0.806, r(2)(pred) = 0.761 for 3'-processing and r(2)(cv) = 0.677, r(2)(pred) = 0.591 for 3'-strand transfer).

Molecular electrostatic potentials as input for the alignment of HIV-1 integrase inhibitors in 3D QSAR.

Comparative molecular similarity indices analysis (CoMSIA), a three-dimensional quantitative structure activity relationship (3D QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities (3'-processing and 3'-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. The training set consisted of 34 molecules from five structurally diverse classes: salicylpyrazolinones, dioxepinones, coumarins, quinones, and benzoic hydrazides. The data set was aligned using extrema of molecular electrostatic potentials (MEPs). The predictive ability of the resultant model was evaluated using a test set comprised of 7 molecules belonging to a different structural class of thiazepinediones. A CoMSIA model using an MEP-based alignment showed considerable internal as well external predictive ability (r2(cv) = 0.821, r2(pred) = 0.608 for 3'-processing; and r2(cv) = 0.759, r2(pred.) = 0.660 for 3'-strand transfer).