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Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches

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Abstract

Chikungunya virus (CHIKV) is the etiological agent of the Chikungunya fever which has spread worldwide. Clinically, this disease may lead to prolonged incapacitating joint pain that can compromise remarkably the patients’ quality of life. However, there are no licensed vaccines or specific drugs to fight this infection yet, making the search for novel therapies an imperative need. In this scenario, the CHIKV nsP2 protease emerged as an attractive therapeutic target once this protein plays a pivotal role in viral replication and pathogenesis. Hence, we investigated the structural basis for the inhibition of this enzyme by using molecular docking and dynamics simulations. Compounds with inhibitory activities against CHIKV nsP2 protease determined experimentally were selected from the literature. Docking studies with a set of stereoisomers showed that trans isomers, but not cis ones, bound close to the catalytic dyad which may explain isomerism requirements to the enzyme’s inhibition. Further, binding mode analyses of other known inhibitors revealed highly conserved contacts between inhibitors and enzyme residues like N1011, C1013, A1046, Y1079, N1082, W1084, L1205, and M1242. Molecular dynamics simulations reinforced the importance of some of these interactions and pointed to nonpolar interactions as the main forces for inhibitors’ binding. Finally, we observed that true inhibitors exhibited lower structural fluctuation, higher ligand efficiency and did not induce significant changes in protein correlated motions. Collectively, our findings might allow discerning true inhibitors from false ones and can guide drug development efforts targeting the nsP2 protease to fight CHIKV infections in the future.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the Laboratório Nacional de Computação Científica, CENAPAD, RJ, for providing high-performance computing resources. Also, we thank Dr. Helena Carla Castro from Universidade Federal Fluminense for supplying computational resources used to execute part of this work.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. In addition, this work was supported by the Brazilian agencies National Council for Scientific and Technological Development (CNPQ) and Research Support Foundation of the State of Rio de Janeiro (FAPERJ).

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Authors and Affiliations

  1. Instituto de Biologia, Programa de Pós-Graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Niterói, RJ, 24210-201, Brazil

    Vitor Won-Held Rabelo & Izabel Christina Nunes de Palmer Paixão

  2. Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, 24210-201, Brazil

    Izabel Christina Nunes de Palmer Paixão

  3. Instituto de Biodiversidade e Sustentabilidade (NUPEM), Universidade Federal do Rio de Janeiro, Macaé, RJ, 27965-045, Brazil

    Paula Alvarez Abreu

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  1. Vitor Won-Held Rabelo
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  3. Paula Alvarez Abreu
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Vitor Won-Held Rabelo. The first draft of the manuscript was written by Vitor Won-Held Rabelo and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Paula Alvarez Abreu.

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Rabelo, V.WH., de Palmer Paixão, I.C.N. & Abreu, P.A. Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches. J Mol Model 28, 311 (2022). https://doi.org/10.1007/s00894-022-05316-3

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