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 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).
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Authors | Eduardo B de Melo, Márcia M C Ferreira |
Journal | Journal of chemical information and modeling
(J Chem Inf Model)
Vol. 52
Issue 7
Pg. 1722-32
(Jul 23 2012)
ISSN: 1549-960X [Electronic] United States |
PMID | 22657398
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-HIV Agents
- HIV Integrase
- p31 integrase protein, Human immunodeficiency virus 1
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Topics |
- Anti-HIV Agents
(chemistry, pharmacology)
- Drug Design
- Enzyme Activation
(drug effects)
- HIV Integrase
(metabolism)
- HIV-1
- Models, Biological
- Molecular Conformation
- Molecular Dynamics Simulation
- Quantitative Structure-Activity Relationship
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