Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/67087
Type: Artigo de periódico
Title: Four-Dimensional Structure-Activity Relationship Model to Predict HIV-1 Integrase Strand Transfer Inhibition using LQTA-QSAR Methodology
Author: de Melo, EB
Ferreira, MMC
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).
Country: EUA
Editor: Amer Chemical Soc
Rights: fechado
Identifier DOI: 10.1021/ci300039a
Date Issue: 2012
Appears in Collections:Artigos e Materiais de Revistas Científicas - Unicamp

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