title: Computational studies on tetrahydropyrimidine-2-one HIV-1 protease inhibitors: improving three-dimensional quantitative structure-activity relationship comparative molecular field analysis models by inclusion of calculated inhibitor- and receptor-based properties.
abstract: A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar buried surface areas (BSAs) with the observed values of the binding affinity (pK(I)). Various combinations of these specific inhibitor- and receptor-based properties were also evaluated as additional descriptors to three-dimensional quantitative structure-activity relationship (3D-QSAR) models constructed using comparative molecular field analysis (CoMFA). Linear regression of the observed pK(I) values with E(compl), E(solv)[I], and the BSAs yielded a strong correlation in terms of both self-consistency (r(2) approximately equal to 0.90) and internal predictive ability (r(cv)(2) > 0.50). The 3D-QSAR models obtained from CoMFA using standard partial least-squares (PLS) analysis also yielded a strong correlation between the CoMFA fields and the experimental pK(i) (r(2) = 0.96; r(cv)(2) = 0.58). Various "enhanced" 3D-QSAR models were constructed in which different combinations of the E(compl), E(solv)[I], and BSAs were added as additional descriptors to the default steric-electrostatic CoMFA fields. Inclusion of E(solv)[I] in particular yielded significant improvement in the predictive ability (r(cv)(2) approximately equal to 0.80) of the resultant 3D-QSAR model.
authors.affiliation: Department of Chemistry & Biochemistry and Center for Molecular Electronics, University of Missouri-St. Louis, St. Louis, MO 63121, USA.
authors.forename: Anil C
authors.initials: AC
authors.lastname: Nair
authors.forename: Philippa
authors.initials: P
authors.lastname: Jayatilleke
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D016333:HIV Protease / Q000737:chemistry*; D008024:Ligands; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D011743:Pyrimidines; D016333:HIV Protease