Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19

  • J Phys Chem Lett. 2021 Feb 25;12(7):1793-1802. doi: 10.1021/acs.jpclett.0c03119.
Suresh Gangadevi  1 ,  Vishnu Nayak Badavath  2 ,  Abhishek Thakur  3 ,  Na Yin  1 ,  Steven De Jonghe  4 ,  Orlando Acevedo  3 ,  Dirk Jochmans  4 ,  Pieter Leyssen  4 ,  Ke Wang  5 ,  Johan Neyts  4 ,  Tao Yujie  6 ,  Galia Blum  2
Affiliations
  • 1. Anhui Provincial Engineering Laboratory of Silicon-Based Materials, Bengbu University, Caoshan Road 1866, Bengbu, Anhui 233030, PR China.
  • 2. Institute for Drug Research, The Hebrew University, Jerusalem 9112001, Israel.
  • 3. Department of Chemistry, University of Miami, Coral Gables, Florida 33146, United States.
  • 4. Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 5. College of Material and Chemical Engineering, Bengbu University, Bengbu 233030, China.
  • 6. East China University of Political Science and Law, Shanghai 20042 China.
PMID: 33577324 DOI: 10.1021/acs.jpclett.0c03119
Abstract

In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC50 of 1.81 ± 0.04 μM and inhibit SARS-CoV-2 viral Infection in cells with an EC50 of 71.6 μM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.

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