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Type: Artigo de periódico
Title: The receptor-dependent LQTA-QSAR: application to a set of trypanothione reductase inhibitors
Author: Barbosa, EG
Pasqualoto, KFM
Ferreira, MMC
Abstract: A new Receptor-Dependent LQTA-QSAR approach, RD-LQTA-QSAR, is proposed as a new 4D-QSAR method. It is an evolution of receptor independent LQTA-QSAR. This approach uses the free GROMACS package to carry out molecular dynamics simulations and generates a conformational ensemble profile for each compound. Such an ensemble is used to build molecular interaction field-based QSAR models, as in CoMFA. To show the potential of this methodology, a set of 38 phenothiazine derivatives that are specific competitive T. cruzi trypanothione reductase inhibitors, was chosen. Using a combination of molecular docking and molecular dynamics simulations, the binding mode of the phenotiazine derivatives was evaluated in a simulated induced fit approach. The ligands alignments were performed using both ligand and binding site atoms, enabling unbiased alignment. The models obtained were extensively validated by leave-N-out cross-validation and y-randomization techniques to test for their robustness and absence of chance correlation. The final model presented Q (2) LOO of 0.87 and RA(2) of 0.92 and a suitable external prediction of = 0.78. The adapted binding site obtained is useful to perform virtual screening and ligand structure-based design and the descriptors in the final model can aid in the design new inhibitors.
Subject: LQTA-QSAR
T. cruzi
Molecular dynamics simulations
Country: Holanda
Editor: Springer
Citation: Journal Of Computer-aided Molecular Design. Springer, v. 26, n. 9, n. 1055, n. 1065, 2012.
Rights: fechado
Identifier DOI: 10.1007/s10822-012-9598-2
Date Issue: 2012
Appears in Collections:Unicamp - Artigos e Outros Documentos

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