In silico exploration of small-molecule α-helix mimetics as inhibitors of SARS-COV-2 attachment to ACE2

Abstract

The novel coronavirus, SARS-CoV-2, has infected more than 10 million people and caused more than 502,539 deaths worldwide as of June 2020. The explosive spread of the virus and the rapid increase in the number of cases require the immediate development of effective therapies and vaccines as well as accurate diagnosis tools. The pathogenesis of the disease is triggered by the entry of SARS-CoV-2 via its spike protein into ACE2-bearing host cells, particularly pneumocytes, resulting in overactivation of the immune system, which attacks the infected cells and damages the lung tissue. The interaction of the SARS-CoV-2 receptor binding domain (RBD) with host cells is primarily mediated by the N-terminal helix of ACE2; thus, inhibition of the spike-ACE2 interaction may be a promising therapeutic strategy for blocking the virus entry into host cells. In this paper, we used an in-silico approach to explore small-molecule α-helix mimetics as inhibitors that may disrupt the attachment of SARS-CoV-2 to ACE2. First, the RBD-ACE2 interface in the 6M0J structure was studied by the MM-GBSA decomposition module of the HawkDock server, which led to the identification of two critical target regions in the RBD. Next, two virtual screening experiments of 7236 α-helix mimetics from ASINEX were conducted on the above regions using the iDock tool, which resulted in 10 candidates with favorable binding affinities. Finally, the stability of RBD complexes with the top-two ranked compounds was further validated by 100 ns of molecular dynamics simulations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coronavirus
• SARS-COV-2
• COVID-19
• treatment
• α-helix mimetics
• ACE2
• spike
• virtual screening
• MD simulation

Conclusion

Given the severity of the SARS-CoV-2 epidemic and the possible emergence of similar coronaviruses from animal reservoirs to cause future pandemics, there is a great need to discover new drugs with novel mechanisms to inhibit viral transmission and processing. In this study, we targeted the RBD of the SARS-CoV-2 with small molecule α-helix mimetics, since its attachment to host cells is primarily mediated by the N-terminal helix of ACE2. The selected candidates have shown strong binding affinities to the critical R1 and R2 regions of RBD. Further validation by MD simulations indicated that complexes of RBD with the most potent compounds were stable and characterized by favorable binding free energy. The tested compounds are available for purchase from ASINEX for further experimental validation of our findings.Acknowledgements

Acknowledgements

We sincerely thank the authors and laboratories around the world who have sequenced and shared the full genome data for SARS-CoV-2 in the GISAID database. All data authors can be contacted directly via www.gisaid.org. This work was carried out under National Funding from the Moroccan Ministry of Higher Education and Scientific Research (Covid-19 Program) to AI. This work was also supported by a grant from Institute of Cancer Research and the PPR-1 program to AI.

Disclosure statement

The authors declare that they have no competing interests.