title: Computational studies on HIV-1 protease inhibitors: influence of calculated inhibitor-enzyme binding affinities on the statistical quality of 3D-QSAR CoMFA models.
abstract: A theoretical study was performed on a set of 38 human immunodeficiency type 1 (HIV-1) protease inhibitors that are structurally similar to the AIDS drug Indinavir. Comparison between the computed binding energies and experimental activity data (pIC(50)) found a high degree of correlation (r(2)() = 0.82). Three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) yielded predicted activities that were in excellent agreement with the corresponding experimentally determined values. Inclusion of the calculated enzyme-inhibitor binding energy as an additional descriptor in the CoMFA model yielded a significant 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 different partial atomic charge assignment schemes (Discover CVFF, Gasteiger-Marsili, and AM1-ESP) on the statistical quality of the models.
authors.affiliation: Department of Chemistry and Center for Molecular Electronics, University of Missouri-St. Louis, St. Louis, Missouri 63121, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Jayatilleke
authors.forename: A C
authors.initials: AC
authors.lastname: Nair
authors.forename: R
authors.initials: R
authors.lastname: Zauhar
authors.forename: W J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019469:Indinavir / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease