Reactivity-guided de novo molecular design and high throughput virtual screening of a targeted library of peptidomimetic compounds reveals charge-based structure-activity relationship of potential covalent inhibitors of the main protease of SARS-CoV-2

Authors

  • Stephanie Sun Center for Advanced Study, Aspiring Scholars Directed Research Program
  • Kavya Anand
  • Ishani Ashok
  • Bhavesh Ashok
  • Ayush Bajaj
  • Varsha Beldona
  • Kushal Chattopadhyay
  • Audrey Kwan
  • Karankumar Mageswaran
  • Anvi Surapaneni
  • Atri Surapaneni
  • Pranjal Verma
  • Allen Chen
  • Ria Kolala
  • Andrew Liang
  • Ayeeshi Poosarla
  • Krithikaa Premnath
  • Karthikha Sri Indran
  • Jeslyn Wu
  • Aishwarya Yuvaraj
  • Harsha Raj
  • Tanish Sathish
  • Aashi Shah
  • Sarah Su
  • Kara Tran
  • Edward Njoo

DOI:

https://doi.org/10.47611/jsrhs.v9i2.1082

Keywords:

COVID-19, SARS-CoV-2, Protease Inhibitors, Computer-Guided Drug Design, Organic Chemistry, Medicinal Chemistry, Antiviral Drugs, Molecular Docking

Abstract

In December of 2019, a novel coronavirus was first identified in Wuhan, China, and has since spread around the world, leaving a largely unsolved biomedical problem in its wake. Upon entry into host cells, the main protease is essential for the replication of viral RNA, which is what allows the virus to replicate inside humans. Inhibition of the main protease has been investigated as a potential strategy for inhibition of the viral replication cycle. Here, we designed a combinatorial library of small molecules and performed high-throughput virtual screening to identify a series of hit compounds that may serve as potential inhibitors of the main protease. In our design of covalent inhibitors of the coronavirus protease, we modeled a library of 361 peptidomimetic Michael acceptor small molecules, which are designed to engage the nucleophilic cysteine residue in the active site of the protease in an irreversible 1,4-conjugate addition. We then employed a variety of computational tools to determine the binding affinity of our designed compounds when bound to the protease active site, where we determined that cationic side chains are potentially beneficial for inhibition of SARS-CoV-2.   

Downloads

Download data is not yet available.

References or Bibliography

Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., … Zhang, Y.-Z. (2020). A new coronavirus associated with human respiratory disease in China. Nature, 579(7798), 265–269. https://doi.org/10.1038/s41586-020-2008-3

Rothan, H. A., & Byrareddy, S. N. (2020). The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity, 109, 102433. https://doi.org/10.1016/j.jaut.2020.102433

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. (2020). Nature Microbiology, 5(4), 536–544. https://doi.org/10.1038/s41564-020-0695-z

Ren, L.-L., Wang, Y.-M., Wu, Z.-Q., Xiang, Z.-C., Guo, L., Xu, T., … Wang, J.-W. (2020). Identification of a novel coronavirus causing severe pneumonia in human. Chinese Medical Journal, 133(9), 1015–1024. https://doi.org/10.1097/cm9.0000000000000722

Fehr, A. R., & Perlman, S. (2015). Coronaviruses: An Overview of Their Replication and Pathogenesis. Coronaviruses Methods in Molecular Biology, 1–23. https://doi.org/10.1007/978-1-4939-2438-7_1

Ramajayam, R., Tan, K.-P., & Liang, P.-H. (2011). Recent development of 3C and 3CL protease inhibitors for anti-coronavirus and anti-picornavirus drug discovery. Biochemical Society Transactions, 39(5), 1371–1375. https://doi.org/10.1042/bst0391371

Dai, W., Zhang, B., Su, H., Li, J., Zhao, Y., Xie, X., … Liu, H. (2020). Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. https://doi.org/10.1126/science.abb4489

Shi, J., & Song, J. (2006). The catalysis of the SARS 3C-like protease is under extensive regulation by its extra domain. FEBS Journal, 273(5), 1035–1045. https://doi.org/10.1111/j.1742-4658.2006.05130.x

Goyal, B., & Goyal, D. (2020). Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy. ACS Combinatorial Science. https://doi.org/10.1021/acscombsci.0c00058

Ton, A.-T., Gentile, F., Hsing, M., Ban, F., & Cherkasov, A. (2020). Rapid Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease by Deep Docking of 1.3 Billion Compounds. Molecular Informatics. https://doi.org/10.1002/minf.202000028

Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., … Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. https://doi.org/10.1126/science.abb3405

Tan, J., George, S., Kusov, Y., Perbandt, M., Anemuller, S., Mesters, J. R., … Hilgenfeld, R. (2013). 3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses. Journal of Virology, 87(8), 4339–4351. https://doi.org/10.1128/jvi.01123-12

Naidu, B. N., Sorenson, M. E., Connolly, T. P., & Ueda, Y. (2003). Michael Addition of Amines and Thiols to Dehydroalanine Amides: A Remarkable Rate Acceleration in Water. The Journal of Organic Chemistry, 68(26), 10098–10102. https://doi.org/10.1021/jo034762z

Zhang, Y., Yang, R., Huang, J., Liang, Q., Guo, Y., Bian, W., … Li, H. (2015). Michael addition of dehydroalanine-containing MAPK peptides to catalytic lysine inhibits the activity of phosphothreonine lyase. FEBS Letters, 589(23), 3648–3653. https://doi.org/10.1016/j.febslet.2015.10.025

Radzicka, A., & Wolfenden, R. (1996). Rates of Uncatalyzed Peptide Bond Hydrolysis in Neutral Solution and the Transition State Affinities of Proteases. Journal of the American Chemical Society, 118(26), 6105–6109. https://doi.org/10.1021/ja954077c

Tugyi, R., Uray, K., Ivan, D., Fellinger, E., Perkins, A., & Hudecz, F. (2005). Partial D-amino acid substitution: Improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proceedings of the National Academy of Sciences, 102(2), 413–418. https://doi.org/10.1073/pnas.0407677102

Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics, 4(1). https://doi.org/10.1186/1758-2946-4-17

Neese, F. (2011). The ORCA program system. WIREs Computational Molecular Science, 2(1), 73–78. https://doi.org/10.1002/wcms.81

Grosdidier, A., Zoete, V., & Michielin, O. (2011). SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Research, 39(suppl). https://doi.org/10.1093/nar/gkr366

Owen, C., Lukacik, P., Strain-Damerell, C., Douangamath, A., Powell, A., Fearon, D., … Walsh, M. (2020). SARS-CoV-2 main protease with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19). https://doi.org/10.2210/pdb6y84/pdb

Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera-A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605–1612. https://doi.org/10.1002/jcc.20084

Published

11-20-2020

How to Cite

Sun, S., Anand , K. ., Ashok, I., Ashok, B. ., Bajaj, A. ., Beldona , V., Chattopadhyay, K., Kwan, A., Mageswaran, K., Surapaneni, A., Surapaneni, A., Verma, P., Chen, A., Kolala, R., Liang, A., Poosarla, A. ., Premnath, K., Sri Indran, K., Wu, J., Yuvaraj, A. ., Raj, H. ., Sathish, T. ., Shah, A. ., Su, . S. ., Tran, K., & Njoo, E. (2020). Reactivity-guided de novo molecular design and high throughput virtual screening of a targeted library of peptidomimetic compounds reveals charge-based structure-activity relationship of potential covalent inhibitors of the main protease of SARS-CoV-2 . Journal of Student Research, 9(2). https://doi.org/10.47611/jsrhs.v9i2.1082

Issue

Section

HS Research Articles