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Molecular docking and dynamic simulations of quinoxaline 1,4-di-N-oxide as inhibitors for targets from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica

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Abstract

Context

Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively.

Methods

Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics’ trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents.

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Data availability

The datasets generated during and/or analyzed during the current study are available in the supplementary material.

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Funding

This work was supported by Secretaria de Investigacion y Posgrado del Instituto Politecnico Nacional (Grants 20220935 and 20230935).

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Authors and Affiliations

  1. Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, 88710, Reynosa, México

    Alonzo González-González, Domingo Méndez-Álvarez, Lenci K. Vázquez-Jiménez, Timoteo Delgado-Maldonado, Eyra Ortiz-Pérez, Alma D. Paz-González & Gildardo Rivera

  2. Department of Chemistry and SEEMS, University of Texas Rio Grande Valley, Edinburg, TX, 78539, USA

    Debasish Bandyopadhyay

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  1. Alonzo González-González
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Alonzo González-González, Domingo Méndez-Álvarez, and Lenci K. Vázquez-Jiménez, Timoteo Delgado-Maldonado, Eyra Ortiz-Pérez, Alma D. Paz-González, Debasish Bandyopadhyay, and Gildardo Rivera. The first draft of the manuscript was written by Alonzo Gonzalez-Gonzalez, and Gildardo Rivera, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Gildardo Rivera.

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González-González, A., Méndez-Álvarez, D., Vázquez-Jiménez, L.K. et al. Molecular docking and dynamic simulations of quinoxaline 1,4-di-N-oxide as inhibitors for targets from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica. J Mol Model 29, 180 (2023). https://doi.org/10.1007/s00894-023-05579-4

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