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Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations

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Abstract

The Hepatitis C Virus (HCV) NS3/4A is an attractive target for the treatment of Hepatitis C infection. Herein, we present an investigation of HCV NS3/4A inhibitors based on a sulfonamidobenzamide scaffold. Inhibitor interactions with HCV NS3/4A were explored by molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations. All of the inhibitors adopt similar molecular docking poses in the catalytic site of the protease that are stabilized by hydrogen bond interactions with G137 and the catalytic S139, which are known to be important for potency and binding stability. The quantitative assessments of binding free energies from MM/PBSA correlate well with the experimental results, with a high coefficient of determination, R2 of 0.92. Binding free energy decomposition analyses elucidate the different contributions of Q41, F43, H57, R109, K136, G137, S138, S139, A156, M485, and Q526 in binding different inhibitors. The importance of these sidechain contributions was further confirmed by computational alanine scanning mutagenesis. In addition, the sidechains of K136 and S139 show crucial but distinct contributions to inhibitor binding with HCV NS3/4A. The structural basis of the potency has been elucidated, demonstrating the importance of the R155 sidechain conformation. This extensive exploration of binding energies and interactions between these compounds and HCV NS3/4A at the atomic level should benefit future antiviral drug design.

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Acknowledgements

We thank ChemAxon for a free academic license of their cheminformatics suite, used for data management. This work was supported in part by NIH grant R41 AI112114. Molecular graphics and analyses were performed with UCSF Chimera (developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311). Access to ICM-Molsoft (version 3.9-2e) was generously provided by Proteco Research LLC. The MD simulations were performed on the UIC Extreme high-performance computing cluster in the UIC Academic Computing and Communications Center. We thank UIC ACCC providing us with access.

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  1. Jinhong Ren

    Present address: BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhong-Guan-Cun Life Sciences Park, Changping District, Beijing, 102206, People’s Republic of China

  2. Jinhong Ren and Tasneem M. Vaid have contributed equally to this work.

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  1. Center for Biomolecular Sciences and Department of Pharmaceutical Sciences, University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL, 60607, USA

    Jinhong Ren, Tasneem M. Vaid, Hyun Lee, Isabel Ojeda & Michael E. Johnson

  2. Biophysics Core at Research Resource Center, University of Illinois at Chicago, 1100 S. Ashland Ave, Chicago, IL, 60607, USA

    Hyun Lee

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All authors contributed to the study conception and design, including material preparation, data collection and analysis. The initial draft of the manuscript was written by JR, with additions and revisions from TMV. HL and MEJ provided comments and edited the manuscript. All authors read and approved the final manuscript.

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Ren, J., Vaid, T.M., Lee, H. et al. Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations. J Comput Aided Mol Des 37, 53–65 (2023). https://doi.org/10.1007/s10822-022-00490-1

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