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Molecules 2012, 17(7), 7666-7694; doi:10.3390/molecules17077666

Residue-Ligand Interaction Energy (ReLIE) on a Receptor-Dependent 3D-QSAR Analysis of S- and NH-DABOs as Non-Nucleoside Reverse Transcriptase Inhibitors

1
Laboratory of Computational Medicinal Chemistry (LabQMC), Faculty of Pharmacy, Fluminense Federal University (UFF), Niterói, RJ, 24241-000, Brazil
2
Laboratory of Molecular Modeling (LabMMol), Program of Post-Graduation in Chemistry (PPGQu), Institute of Chemistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-909, Brazil
3
Laboratory of Molecular Modeling & QSAR (ModMolQSAR), Faculty of Pharmacy, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, 21941-590, Brazil
4
Laboratory of Antibiotics, Biochemistry, Education and Molecular Modeling (LABiEMol), Institute of Biology, Fluminense Federal University (UFF), Niterói, RJ, 24210-130, Brazil
Current address: CENPES/PETROBRAS, Av. Horácio Macedo 950, Cidade Universitária, Rio de Janeiro, RJ, 21941-915, Brazil.
*
Authors to whom correspondence should be addressed.
Received: 7 May 2012 / Revised: 2 June 2012 / Accepted: 5 June 2012 / Published: 25 June 2012
(This article belongs to the Section Medicinal Chemistry)
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Abstract

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by receptor-dependent (RD) three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to derive RD-3D-QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue) simulated by molecular dynamics, an approach named Residue-Ligand Interaction Energy (ReLIE). This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference. The ReLIE-3D-QSAR models were constructed and evaluated by genetic algorithm (GA) and partial least squares (PLS). In the best equations, at least one term is related to one of the amino acid residues of the p51 subunit: Asn136, Asn137, Glu138, and Thr139. This fact implies the importance of interchain interaction (p66-p51) in the equations that best describe the structure-activity relationship for this class of compounds. The best equation shows q2 = 0.660, SEcv = 0.500, r2 = 0.930, and SEE = 0.226. The external predictive ability of this best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, substituents capable of interactions with residues like Ile94, Lys101, Tyr181, and Tyr188 should be selected. Also, given the importance of the conserved Asn136, this residue could become an attractive target for the design of novel NNRTIs with improved potency and increased ability to avoid the development of drug-resistant viruses.
Keywords: receptor-dependent 3D-QSAR; residue-ligand interaction energy; molecular dynamics; DABO derivatives; reverse transcriptase; AIDS/HIV-1 receptor-dependent 3D-QSAR; residue-ligand interaction energy; molecular dynamics; DABO derivatives; reverse transcriptase; AIDS/HIV-1
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MDPI and ACS Style

de Brito, M.A.; Rodrigues, C.R.; Cirino, J.J.V.; Araújo, J.Q.; Honório, T.; Cabral, L.M.; de Alencastro, R.B.; Castro, H.C.; Albuquerque, M.G. Residue-Ligand Interaction Energy (ReLIE) on a Receptor-Dependent 3D-QSAR Analysis of S- and NH-DABOs as Non-Nucleoside Reverse Transcriptase Inhibitors. Molecules 2012, 17, 7666-7694.

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