Pathway enrichment analysis of virus-host interactome and prioritization of novel compounds targeting the spike glycoprotein receptor binding domain–human angiotensin-converting enzyme 2 interface to combat SARS-CoV-2

Abstract

SARS-CoV-2 has become a pandemic causing a serious global health concern. The absence of effective drugs for treatment of the disease has caused its rapid spread on a global scale. Similarly to the SARS-CoV, the SARS-CoV-2 is also involved in a complex interplay with the host cells. This infection is characterized by a diffused alveolar damage consistent with the Acute Respiratory Disease Syndrome (ARDS). To explore the complex mechanisms of the disease at the system level, we used a network medicine tools approach. The protein-protein interactions (PPIs) between the SARS-CoV and the associated human cell proteins are crucial for the viral pathogenesis. Since the cellular entry of SARS-CoV-2 is accomplished by binding of the spike glycoprotein binding domain (RBD) to the human angiotensin-converting enzyme 2 (hACE2), a molecule that can bind to the spike RDB-hACE2 interface could block the virus entry. Here, we performed a virtual screening of 55 compounds to identify potential molecules that can bind to the spike glycoprotein and spike-ACE2 complex interface. It was found that the compound ethyl 1-{3-[(2,4-dichlorobenzyl) carbamoyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolinyl}-4-piperidine carboxylate (the S54 ligand) and ethyl 1-{3-[(2,4-dichlorobenzyl) carbamoyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolinyl}-4 piperazine carboxylate (the S55 ligand) forms hydrophobic interactions with Tyr41A, Tyr505B and Tyr553B, Leu29A, Phe495B, respectively of the spike glycoprotein, the hotspot residues in the spike glycoprotein RBD-hACE2 binding interface. Furthermore, molecular dynamics simulations and free energy calculations using the MM-GBSA method showed that the S54 ligand is a stronger binder than a known SARS-CoV spike inhibitor SSAA09E3 (N-(9,10-dioxo-9, 10-dihydroanthracen-2-yl) benzamide).

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• protein–protein interactions (PPIs)
• spike glycoprotein
• virtual screening
• molecular docking
• molecular dynamics

Acknowledgements

The authors are thankful to Registrar, Nitte (Deemed to be University), Mangalore, India for providing all the facilities to complete this work. The authors also acknowledge the University of Zagreb, University Computing Centre (SRCE) for granting computational time on the ISABELLA cluster.

CRediT authorship contribution statement

P.G., S.B.S., P.K.S. conceived and planned the experiments.

P.G., S.B.S. carried out the experiments.

H.R. carried out all MD simulations and MM-GBSA calculations

P.G., S.B.S., P. P., S. K., S.K., P.K.S. contributed to the interpretation of the results. P.G., and S.B.S. took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).