title: Comparative molecular field analysis of a series of inhibitors of HIV-1 protease.
abstract: Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.
authors.affiliation: Laboratório de Química Medicinal e Computacional, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, 13560-970, São Carlos-SP, Brazil.
authors.forename: Leonardo G
authors.initials: LG
authors.lastname: Ferreira
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
authors.forename: Adriano D
authors.initials: AD
authors.lastname: Andricopulo
mesh_terms: D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease