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Studies of NMR, molecular docking, and molecular dynamics simulation of new promising inhibitors of cruzaine from the parasite Trypanosoma cruzi

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Abstract

Cruzaine is the major cysteine protease of Trypanosoma cruzi. Cruzaine is involved throughout the parasite’s life cycle in host cells, and is a promising target in the search for new antichagasic agents. Quantum chemical calculations based on density functional theory (DFT B3LYP/cc-pVDZ) were performed to obtain nuclear magnetic resonance data and to optimize the geometry of four dihydrochalcones. The results showed good agreement with the experimental data and were used to suggest the relative stereochemistry of one of the four dihydrochalcones studied. In addition, we evaluated the interaction of cruzaine with these new inhibitors. We used molecular dynamics simulations, free energy calculations, and a per-residue energy decomposition method. It was observed that these molecules are capable of interacting with residues important for enzymatic activity, like Cys25, His161, and Asp160. The ranking of the inhibitors obtained from the binding free energy calculations is in agreement with that experimentally reported. The evaluation of the energy components involved in these calculations demonstrated that the van der Waals term is the major contributor to the drug–receptor stabilizing interactions.

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Acknowledgements

Jorddy N. Cruz appreciate the support of the Federal University of Pará and the National Council for Scientific and Technological Development (CNPq). Conflict of interest The authors declare that there is no conflict of interest regarding the publication of this paper.

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Authors and Affiliations

  1. Federal Institute of Pará, Parauapebas, PA, 68515-000, Brazil

    Renato A. Costa

  2. Post-Graduate Program in Chemistry, Federal University of Pará, Belém, PA, 66075-110, Brazil

    Renato A. Costa, Fabiana C. A. Nascimento, Sebastião G. Silva, Silvana O. Silva, Marlice C. Martelli, Samira M. L. Carvalho & Davi S. B. Brasil

  3. Laboratory of Preparation and Computation of Nanomaterials, Federal University of Pará, Belém, PA, 66075-110, Brazil

    Jorddy N. Cruz & Antonio M. J. C. Neto

  4. Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, AP, 68902-280, Brazil

    Cleydson B. R. Santos

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  1. Renato A. Costa
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Costa, R.A., Cruz, J.N., Nascimento, F.C.A. et al. Studies of NMR, molecular docking, and molecular dynamics simulation of new promising inhibitors of cruzaine from the parasite Trypanosoma cruzi. Med Chem Res 28, 246–259 (2019). https://doi.org/10.1007/s00044-018-2280-z

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