Docking and molecular dynamics studies of human ezrin protein with a modelled SARS-CoV-2 endodomain and their interaction with potential invasion inhibitors

Human ezrin protein interacts with SARS-CoV S endodomain and restricts virus fusion, entry, and early events of infection. In general, their binding strength and their structural stability determines their suc-cessful entry into the host cells. However, the binding affinity of these two endodomains with the ezrin protein has been elusive due to a paucity of knowledge on the 3D structure. This study modelled the endodomains of both SARS-CoV-1 and SARS-CoV-2 and then docked these models with human ezrin pro-tein. This study establishes that the modelled endodomains of both SARS-CoV-1 and SARS-Cov-2 con-sisted of three disulphide bridges for self-stabilization. Protein-protein docking listed four salt bridges with a higher buried surface area between ezrin-SARS-CoV-1 endodomain compared to that of ezrin-SARS-CoV-2 with six salt bridges with lower buried surface area. Molecular simulation of the ezrin-SARS-CoV-1 endodomain showed better structural stability with lower Root Mean Square Deviation score compared to that of ezrin-SARS-CoV-2 endodomain due to the substitution of alanine with cysteine resi-due. Protein-ligand docking studies confirmed better ezrin-drug interaction for quercetin, minocycline, calcifediol, calcitriol, selamectin, ivermectin and ergocalciferol. However, protein-ligand simulation con-firmed strong drug-protein interaction during simulation for all the above-listed drugs except for ergo-calciferol which could not establish its interaction with the protein during simulation. Strong drug binding within the active site pocket therefore restricts the interaction of viral endodomain and simulta-neously stabilizes the ezrin protein. Furthermore, the higher stability between the ezrin after their inter-action with the drug moiety could restrict the virus fusion and the infection. This study provides a basis for further development of these drug molecules to clinical trials aiming to identify potential drug mole-cules which can treat COVID-19 infection. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).