Four-dimensional structure-activity relationship model to predict HIV-1 integrase strand transfer inhibition using LQTA-QSAR methodology.
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 β-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 (R2= 0.897, SEC = 0.270, and F = 72.827), good performance in internal (QLOO2 = 0.842 and SEV = 0.314) and external prediction (Rpred2 = 0.839, SEP = 0.384, AREpred = 4.942%, k = 0.981, k′ = 1.016, and |R02 – R0′2 = 0.0257). The QSAR model was shown to be robust (leave-N-out cross validation; average QLNO2 = 0.834) and was not built by chance (y-randomization test; R2 intercept = 0.109; Q2 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).
Theoretical Medicinal and Environmental Chemistry Laboratory (LQMAT), Department of Pharmacy, Western Parana State University-Unioeste, 2069 Universitaria St, Cascavel, PR 85819-110, Brazil.
Eduardo B
EB
de Melo
Márcia M C
MM
Ferreira
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D019427:HIV Integrase / Q000378:metabolism*; D015497:HIV-1; D008954:Models, Biological; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship
D019380:Anti-HIV Agents; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1