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Computer-aided design, synthesis and evaluation of new SARS-CoV-2 Mpro inhibitors based on 1,5,6,7-tetrahydro-4H-indazol-4-one scaffold

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Abstract

A novel class of SARS-CoV-2 main protease (Mpro) inhibitors derived from 1,5,6,7-tetrahydro-4H-indazol-4-ones was designed. Virtual screening based on molecular docking followed by molecular dynamics simulation and MM/GBSA calculations was used for selecting compounds for synthesis and an evaluation. After testing 29 prepared compounds for activity against Mpro, two hits with IC50 values bellow 60 μM were found with the best result of 27.31 μM for racemic amide 9m. SAR and further possibilities for hit optimization were discussed. The effectiveness of different approaches (MM/GBSA and alchemical ABFE) for protein–ligand binding affinity prediction was assessed on the basis of obtained experimental data. The best convergence was achieved when we carried out long molecular dynamics simulations (200 ns) of complexes from docking followed by calculations of free binding energies with MM/GBSA method and explicit accounting of entropy.

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Acknowledgements

This work was supported by the Belarusian Republican Foundation for Basic Research (project Х21КОВИД-003). YAP would like to thank Anatoli A. Piven for assistance in automation of virtual screening processes.

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Authors and Affiliations

  1. Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Akad. Kuprevicha st. 5/2, Minsk, 220084, Belarus

    Yuri A. Piven, Veronica G. Zinovich, Tatyana S. Khlebnicova & Fedor A. Lakhvich

  2. Altay State University, Leninski pr. 61, Barnaul, 656049, Russian Federation

    Dmitriy N. Shcherbakov & Varvara Yu. Chirkova

  3. State Research Center of Virology and Biotechnology “Vector”, Koltsovo, 630559, Russian Federation

    Dmitriy N. Shcherbakov & Svetlana V. Belenkaya

  4. Health Care Institution “National Anti-Doping Laboratory”, Minsk District, Borovlyansky s/s, 106-1, district of the village Lesnoy, 223040, Belarus

    Raman M. Puzanau

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  1. Yuri A. Piven
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  2. Veronica G. Zinovich
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Piven, Y.A., Zinovich, V.G., Shcherbakov, D.N. et al. Computer-aided design, synthesis and evaluation of new SARS-CoV-2 Mpro inhibitors based on 1,5,6,7-tetrahydro-4H-indazol-4-one scaffold. Med Chem Res 33, 151–163 (2024). https://doi.org/10.1007/s00044-023-03174-z

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