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The receptor-dependent LQTA-QSAR: application to a set of trypanothione reductase inhibitors

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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 R² of 0.92 and a suitable external prediction of \( Q_{ext}^{2} \)= 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.

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Acknowledgments

The authors thank the Brazilian scientific funding agencies, CAPES and FAPESP, for financial support and Prof. Dr. Carol H. Collins for English revision.

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Authors and Affiliations

  1. Chemistry Institute, University of Campinas (UNICAMP), POB 6154, Campinas, SP, 13083-970, Brazil

    Euzébio G. Barbosa & Márcia M. C. Ferreira

  2. Butantan Institute, São Paulo, SP, Brazil

    Kerly Fernanda M. Pasqualoto

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  1. Euzébio G. Barbosa
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  2. Kerly Fernanda M. Pasqualoto
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  3. Márcia M. C. Ferreira
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Correspondence to Márcia M. C. Ferreira.

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Barbosa, E.G., Pasqualoto, K.F.M. & Ferreira, M.M.C. The receptor-dependent LQTA-QSAR: application to a set of trypanothione reductase inhibitors. J Comput Aided Mol Des 26, 1055–1065 (2012). https://doi.org/10.1007/s10822-012-9598-2

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