Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules

Abstract

Comparative molecular field analysis (CoMFA), a three-dimensional, quantitative structure-activity relationship (QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities of a series of human immunodeficiency virus (HIV-1) protease inhibitors. The training set consisted of 59 molecules from five structurally-diverse transition-state isostere classes: hydroxyethylamine, statine, norstatine, keto amide, and dihydroxyethylene. The availability of X-ray crystallographic data for at least one representative from each class bound to the protease provided information regarding not only the active conformation of each ligand but also, via superimposition of protease backbones, the relative positions of each ligand with respect to one another in the active site of the enzyme. Once aligned, these molecules served as templates on which additional congeners were field-fit minimized. Additional alignment rules were derived from minimizations of the ligands in the active site of the semirigid protease. The predictive ability of each resultant model was evaluated using a test set comprised of molecules containing a novel transition-state isostere: hydroxyethylurea. Crystallographic studies (Getman, D. P.; et al. J. Med. Chem. 1993, 36, 288-291) indicated an unexpected binding mode for this series of compounds which precluded the use of the field-fit minimization alignment technique. The test set molecules were, therefore, subjected to a limited systematic search in conjunction with active-site minimization. The conformer of each molecule expressing the lowest interaction energy with the active site was included in the test set. Field-fit minimization of neutral molecules to crystal ligands and active-site minimizations of protonated ligands yielded predictive correlations for HIV-1 protease inhibitors. The use of crystallographic data in the determination of alignment rules and field-fit minimization as a molecular alignment tool in the absence of direct experimental data regarding binding modes is strongly supported by these results.

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

“…To overcome these difficulties, in 1993 Marshall and coworkers proposed the utilization of alignment techniques based on binding site geometries and minimizations within binding sites as effective alternatives to conformational searches and superimpositions solely based on the molecular properties of the ligands [81,82]. In the following years, with the development of sophisticated automatic docking algorithms and programs, this combined approach became increasingly more feasible and appealing.…”

Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV‐1 protease inhibitors. A 3D‐QSAR‐CoMFA method for new antiviral drug design

“…The statistical parameters: PRESS (Predictable Residual Sum Squares), SD (standard deviation) and q2 [13,15,34,35] were obtained by leave-one-out cross-validation technique [13,15,33]. We considered that the leave-one-out cross-validation technique, which is known to be more suitable than other statistical techniques, is more appropriate for calculation of statistical parameters in our CoMFA study, kept into account that the HIV-1 PR inhibitors present different chemical types of radicals.…”

“…The resistance of the HIV-1 PR mutants obliged us to apply very fast and precise techniques, able to predict the biological activity for the new HIV-1 PR inhibitors. QSAR (quantitative structureactivity relation) techniques [12][13][14], especially 3D-QSAR-CoMFA (Comparative Molecular Field Analysis) or 3D-QSAR-CoMSIA (Comparative Molecular Similarity Analysis) [15][16][17][18][19][20] proved to be very useful when the HIV-1 PR inhibitors potency are to be predicted. In the last years, a good correlation between the predicted and the observed biological activity for the HIV-1 PR cyclic urea inhibitors was reported [16,20,21].…”

Human protein tyrosine phosphatase 1B inhibitors: QSAR by genetic function approximation

“…The predictive r 2 was based only on molecules not included in the training set and is defined as: r 2 pred ¼ ðSD 2 PRESSÞ=SD, where SD is the sum of cv the predictive r 2 can assume a negative value reflecting a complete lack of predictive ability of the training set for the molecules included in the test set [27,28].…”