Discovery of Withaphysalin A and Limonin as Potential SARS-COV2 Papain-Like Protease Inhibitors
DOI:
https://doi.org/10.2200/aerj.v5i1.56Abstract
Protease inhibitors are strategically and functionally important components of drug-hunters’ arsenal against pathogenic viruses including SARS-COV2, SARS-COV, MERS, Ebola and HIV. Drug discovery efforts reported in this work target the papain-like protease (PLpro) alias non-structural protein 3 (nsp3) of SARS-COV2. An in-house database comprising of 6264 phytochemicals derived from 1560 Kenyan medicinal plants, as well as the COCONUT-Mitishamba database provided phytochemical scaffolds used in this in silico structure-based virtual screening study. Overall, 170 phytochemicals from our in-house database and 58 phytochemicals from the COCONUT-Mitishamba database had desirable binding affinities of less than -9.0 kcal/mol. Withaphysalin A (11.5 kcal/mol) and Limonin (-11.1 kcal/mol) are the best compounds targeting the nsp3 of SARS-COV2 from our in-house database. We studied protein-ligand interactions of top-binding molecules to gain insight on their potential modulatory effects on the SARS-COV2 virus. Although experimental validation of the results obtained and other further tests need to be done, these findings will accelerate the drug design and development process.
References
Abraham M.J., T. Murtola, R. Schulz, S. Páll, J.C. Smith, B. Hess, and E. Lindahl, “GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers,” SoftwareX, 1–2 19–25 (2015).
Anirudhan, V., Lee, H., Cheng, H., Cooper, L., & Rong, L. (2021). Targeting SARS-CoV-2 viral proteases as a therapeutic strategy to treat COVID-19. Journal of medical virology, 93(5), 2722–2734. https://doi.org/10.1002/jmv.26814
Bafna, K., White, K., Harish, B., Rosales, R., Ramelot, T. A., Acton, T. B., Moreno, E., Kehrer, T., Miorin, L., Royer, C. A.,
García-Sastre, A., Krug, R. M., & Montelione, G. T. (2021). Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. Cell reports, 35(7), 109133. https://doi.org/10.1016/j.celrep.2021.109133
Boras, B., Jones, R. M., & Anson, B. J. (2021). Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nat Commun. 2021;12(1):6055. Published 2021 Oct 18. doi:10.1038/s41467-021-26239-2
Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7, 42717 (2017). https://doi.org/10.1038/srep42717
Dallakyan, S, Olson, A. J. (2015). Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015;1263:243-50. doi: 10.1007/978-1-4939-2269-7_19. PMID: 25618350.
Fu, Z., Huang, B., Tang, J., Liu, S., Liu, M., Ye, Y., Liu, Z., Xiong, Y., Zhu, W., Cao, D., Li, J., Niu, X., Zhou, H., Zhao, Y. J.,
Zhang, G., & Huang, H. (2021). The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery. Nature communications, 12(1),488. https://doi.org/10.1038/s41467-020-20718-8
Gil, C., Ginex, T., Maestro, I., Nozal, V., Barrado-Gil, L., Cuesta-Geijo, M. Á., Urquiza, J., Ramírez, D., Alonso, C., Campillo, N. E., Martinez, A. (2020). COVID-19: Drug Targets and Potential Treatments. J Med Chem. 2020 Nov 12;63(21):12359-12386. doi: 10.1021/acs.jmedchem.0c00606. Epub 2020 Jun 26. PMID: 32511912; PMCID: PMC7323060.
Jade, D., Ayyamperumal, S., Tallapaneni, V., Joghee Nanjan, C. M., Barge, S., Mohan, S., & Nanjan, M. J. (2021). Virtual high throughput screening: Potential inhibitors for SARS-CoV-2 PLPRO and 3CLPRO proteases. European journal of pharmacology, 901, 174082. https://doi.org/10.1016/j.ejphar.2021.174082
Jamalan, M., Barzegari, E., & Gholami-Borujeni, F. (2021). Structure-Based Screening to Discover New Inhibitors for Papain-like Proteinase of SARS-CoV-2: An In Silico Study. Journal of proteome research, 20(1),1015–1026. https://doi.org/10.1021/acs.jproteome.0c00836
Jiang, H., Yang, P., Zhang, J. (2022). Potential Inhibitors Targeting Papain-Like Protease of SARS-CoV-2: Two Birds With One Stone. Front Chem. 2022 Feb 23;10:822785. doi: 10.3389/fchem.2022.822785. PMID: 35281561; PMCID: PMC8905519.
Khataniar, Ankita, Upasana Pathak, Sanchaita Rajkhowa, & Anupam N. Jha. (2022). "A Comprehensive Review of Drug Repurposing Strategies against Known Drug Targets of COVID-19" COVID 2, no. 2: 148-167. https://doi.org/10.3390/covid2020011
Klemm, T., Ebert, G., Calleja, D. J., Allison, C. C., Richardson, L. W., Bernardini, J. P., Lu, B. G., Kuchel, N. W., Grohmann, C., Shibata, Y., Gan, Z. Y., Cooney, J. P., Doerflinger, M., Au, A. E., Blackmore, T. R., van der Heden van Noort, G. J., Geurink, P. P., Ovaa, H., Newman, J., Riboldi-Tunnicliffe, A., & … Komander, D. (2020). Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. The EMBO journal, 39(18), e106275. https://doi.org/10.15252/embj.2020106275
Lamb, Y. N. (2022). Nirmatrelvir Plus Ritonavir: First Approval. Drugs, 1–7. Advance online publication. https://doi.org/10.1007/s40265-022-01692-5
Lim, C. T., Tan, K. W., Wu, M., Ulferts, R., Armstrong, L. A., Ozono, E., Drury, L. S., Milligan, J. C., Zeisner, T. U., Zeng, J., Weissmann, F., Canal, B., Bineva-Todd, G., Howell, M., O'Reilly, N., Beale, R., Kulathu, Y., Labib, K., & Diffley, J. (2021). Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease. The Biochemical journal, 478(13),2517–2531. https://doi.org/10.1042/BCJ20210244
Ma, C., Sacco, M. D., Xia, Z., Lambrinidis, G., Townsend, J. A., Hu, Y., Meng, X., Szeto, T., Ba, M., Zhang, X., Gongora, M., Zhang, F., Marty, M. T., Xiang, Y., Kolocouris, A., Chen, Y., & Wang, J. (2021). Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay. ACS central science, 7(7), 1245–1260. https://doi.org/10.1021/acscentsci.1c00519
Mattoo, S-u-S., Kim, S-J., Ahn, D-G., & Myoung. J. (2022). Escape and Over-Activation of Innate Immune Responses by SARS-CoV-2: Two Faces of a Coin. Viruses. 2022; 14(3):530. https://doi.org/10.3390/v14030530.
Moustaqil, M., Ollivier, E., Chiu, H. P., Van Tol, S., Rudolffi-Soto, P., Stevens, C., Bhumkar, A., Hunter, D., Freiberg, A. N., Jacques, D., Lee, B., Sierecki, E., & Gambin, Y. (2021). SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species. Emerging microbes & infections, 10(1),178–195. https://doi.org/10.1080/22221751.2020.1870414
Osipiuk, J., Azizi, S. A., Dvorkin, S., Endres, M., Jedrzejczak, R., Jones, K. A., Kang, S., Kathayat, R. S., Kim, Y., Lisnyak, V. G., Maki, S. L., Nicolaescu, V., Taylor, C. A., Tesar, C., Zhang, Y. A., Zhou, Z., Randall, G., Michalska, K., Snyder, S. A., Dickinson, B. C., … Joachimiak, A. (2021). Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nature communications, 12(1), 743. https://doi.org/10.1038/s41467-021-21060-3
Pitsillou, E., Liang, J., Ververis, K., Lim, K. W., Hung, A., & Karagiannis, T. C. (2020). Identification of Small Molecule Inhibitors of the Deubiquitinating Activity of the SARS-CoV-2 Papain-Like Protease: in silico Molecular Docking Studies and in vitro Enzymatic Activity Assay. Frontiers in chemistry, 8, 623971. https://doi.org/10.3389/fchem.2020.623971
Raj, K., Kaur, K., Gupta, G. D., & Singh, S. (2021). Current understanding on molecular drug targets and emerging treatment strategy for novel coronavirus-19. Naunyn Schmiedebergs Arch Pharmacol. 2021;394(7):1383-1402. doi:10.1007/s00210-021-02091-5
Recovery Collaborative Group (2020). Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet (London, England), 396(10259), 1345–1352. https://doi.org/10.1016/S0140-6736(20)32013-4
Rut, W., Lv, Z., Zmudzinski, M., Patchett, S., Nayak, D., Snipas, S. J., El Oualid, F., Huang, T. T., Bekes, M., Drag, M., & Olsen, S. K. (2020). Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design. Science advances, 6(42),eabd4596. https://doi.org/10.1126/sciadv.abd4596
Schrödinger, L., & DeLano, W. (2020). PyMOL. Retrieved from http://www.pymol.org/pymol
Shen, Z., Ratia, K., Cooper, L., Kong, D., Lee, H., Kwon, Y., Li, Y., Alqarni, S., Huang, F., Dubrovskyi, O., Rong, L., Thatcher, G., & Xiong, R. (2021). Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity. Journal of medicinal chemistry, acs.jmedchem.1c01307. Advance online publication. https://doi.org/10.1021/acs.jmedchem.1c01307
Shin, D., Mukherjee, R., Grewe, D., Bojkova, D., Baek, K., Bhattacharya, A., Schulz, L., Widera, M., Mehdipour, A. R., Tascher, G., Geurink, P. P., Wilhelm, A., van der Heden van Noort, G. J., Ovaa, H., Müller, S., Knobeloch, K. P.,
Rajalingam, K., Schulman, B. A., Cinatl, J., Hummer, G., & Dikic, I. (2020). Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature, 587(7835), 657–662. https://doi.org/10.1038/s41586-020-2601-5
Sorokina, M., Merseburger, P., & Rajan, K. (2021). COCONUT online: Collection of Open Natural Products database. J Cheminform 13, . https://doi.org/10.1186/s1,3321-020-00478-9
Stader, F., Khoo, S., Stoeckle, M., Back, D., Hirsch, H. H., Battegay, M., & Marzolini, C. (2020). Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect. J Antimicrob Chemother. 2020 Oct 1;75(10):3084-3086. doi: 10.1093/jac/dkaa253. PMID: 32556272; PMCID: PMC7337877.
Trott, O., & Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of computational chemistry, 31(2), 455-461.
Virdi, S. R., Bavisotto, V. R., Hopper, C. N., & Frick, N. D. (2020). Discovery of Drug-like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3. doi: https://doi.org/10.1101/2020.07.06.190413.
Weglarz-Tomczak, E., Tomczak, J. M., Talma, M., Burda-Grabowska, M., Giurg, M., & Brul, S. (2021). Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2. Scientific reports, 11(1), 3640. https://doi.org/10.1038/s41598-021-83229-6
Xu, Y., Chen, K., Pan, J., Lei, Y., Zhang, D., Fang, L., Tang, J., Chen, X., Ma, Y., Zheng, Y., Zhang, B., Zhou, Y., Zhan, J., &
Xu, W. (2021). Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease. International journal of biological macromolecules, 188,137–146. https://doi.org/10.1016/j.ijbiomac.2021.07.184
Yan, F., & Gao, F. (2021). An overview of potential inhibitors targeting non-structural proteins 3 (PLpro and Mac1) and 5 (3CLpro/Mpro) of SARS-CoV-2. Computational and structural biotechnology journal, 19, 4868–4883. https://doi.org/10.1016/j.csbj.2021.08.036
Zhao, Y., Du, X., Duan, Y., Pan, X., Sun, Y., You, T., Han, L., Jin, Z., Shang, W., Yu, J., Guo, H., Liu, Q., Wu, Y., Peng, C., Wang, J., Zhu, C., Yang, X., Yang, K., Lei, Y., Guddat, L. W., & Yang, H. (2021). High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein & cell, 12(11), 877–888. https://doi.org/10.1007/s13238-021-00836-9
