Four-Dimensional Structure-Activity Relationship Model to Predict HIV-1 Integrase Strand Transfer Inhibition using LQTA-QSAR Methodology

Author(s)

de Melo, Eduardo B. ^[1] ; Ferreira, Marcia M. C. ^[2]

Affiliation

^[1] Western Parana State Univ Unioeste, Dept Pharm, Theoret Med & Environm Chem Lab LQMAT, BR-85819110 Cascavel, PR - Brazil

^[2] Univ Campinas UNICAMP, Inst Chem, Lab Theoret & Appl Chemometr LQTA, BR-13084971 Campinas, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 52, n. 7, p. 1722-1732, JUL 2012.
• Web of Science Citations: 13

Abstract

Despite highly active antiretroviral therapy (HAART) implementation, there is a continuous need to search for new anti-HIV agents. HIV-1 integrase (HIV-1 IN) is a recently validated biological target for AIDS therapy. In this work, a four-dimensional quantitative structure-activity relationship (4D-QSAR) study using the new methodology named LQTA-QSAR approach with a training set of 85 HIV-1 IN strand transfer inhibitors (INSTI), containing the beta-diketo acid (DKA) substructure, was carried out. The GROMACS molecular dynamic package was used to obtain a conformational ensemble profile (CEP) and LQTA-QSAR was employed to calculate Coulomb and Lennard-Jones potentials and to generate the field descriptors. The partial least-squares (PLS) regression model using 14 field descriptors and 8 latent variables (LV) yielded satisfactory statistics (R-2 = 0.897, SEC = 0.270, and F = 72.827), good performance in internal (Q(LOO)(2) = 0.842 and SEV = 0.314) and external prediction (R-pred(2) = 0.839, SEP = 0.384, ARE(pred) = 4.942%, k = 0.981, k' = 1.016, and |R-0(2) - R-0'(2) = 0.0257). The QSAR model was shown to be robust (leave-N-out cross validation; average Q(LNO)(2) = 0.834) and was not built by chance (y-randomization test; R-2 intercept = 0.109; Q(2) intercept = -0.398). Fair chemical interpretation of the model could be traced, including descriptors related to interaction with the metallic cofactors and the hydrophobic loop. The model obtained has a good potential for aid in the design of new INSTI, and it is a successful example of application of LQTA-QSAR as an useful tool to be used in computer-aided drug design (CADD). (AU)

• FAPESP's process: 04/04686-5 - Classic and new chemiometric approaches in theoretic studies of bioactive substances
• Grantee: Marcia Miguel Castro Ferreira
• Support Opportunities: Research Projects - Thematic Grants