Network Proteins of Angiotensin-converting Enzyme 2 But Not Angiotensin-converting Enzyme 2 itself are Host Cell Receptors for SARS-Coronavirus-2 Attachment

Background: Coronaviruses causing severe acute respiratory syndrome (SARS-CoV) are known to enter the host cells by attaching to the membrane bound angiotensin-converting enzyme 2 (ACE2). Using molecular docking the efficiency of interaction between SARS-CoV-2 surface proteins and ACE2 network proteins was assessed. Materials and Methods: The ACE2 protein network was identified using the STRING database. The reported SARS-CoV-2 target proteins were searched in the protein data bank and uniport database. The protein-protein interactions were assessed by molecular docking using the Chimera software. The PubChem database was searched for known inhibitors of host cell receptors interacting with SARS-CoV-2 surface proteins. Molecular docking was performed to evaluate the binding efficacy of these compound sagainst the SARS-CoV-2 targets using AutoDock Vina and the docked protein-ligand complex were visualised using the Chimera and PyMOL software. Results: A lowbinding affinity was observed between SARS-CoV-2 spike proteins (protein S, M and 6YLA) and ACE2. Coronaviruses are also reported to bind to dipeptidyl peptidase 4 (DPP4), which is a network protein of ACE2. Network analysis showed five membrane proteins associated with ACE2. The ACE2 network proteins were assessed for their binding affinity with all known SARS-CoV-2 surface proteins. The SARS-CoV-2 surface proteins showed preferential binding to network proteins such as DPP4 and Meprin A alpha but not ACE2. The binding efficacy (affinity (-5.86 to -7.10 Kcal/mol), Ki (6.32 – 22.04M) and IC₅₀ (12.63 – 113.71M) values) of DPP4 inhibitors (saxagliptin and sitagliptin) against SARS-CoV-2 surface proteins, was observed to be at a therapeutically feasible concentration to prevent SARS-CoV-2 attachment and entry into host cells. Conclusion: SARS-CoV-2 surface proteinshas better interactions with DPP4 and Meprin A alpha host cells receptors rather than ACE2. DPP4 inhibitors (saxagliptin and sitagliptin) by binding with SARS-CoV-2 surface proteins may be helpful in preventing the virus entry into the host cells.