The Computational Intervention of Macrolide Antibiotics in the Treatment of COVID-19.

Abstract

The spike (S) glycoprotein of SARS corona virus (SARS-CoV-2) and human Angiotensin- converting enzyme 2 (ACE2), are both considered the key factors for the initiation of virus infection. The present work is an effort for computational target to block the spike proteins (S) and ACE2 receptor proteins with Macrolide antibiotics like Azithromycin, (AZM), Clarithromycin (CLAM) and Erythromycin (ERY) along with RNA-dependent RNA polymerase (RdRp). Three-dimensional structure of the SARS-CoV-2RdRp was built by the SWISS-MODEL server, the generated structure showed 96.35% identity to the available structure of SARS-Coronavirus NSP12 (6NUR), for model validity, we utilized the SWISS-model server quality parameters and Ramachandran plots. These compounds were able to block the residues (Arg553, Arg555, and Ala558) surrounding the deep grove catalytic site (Val557) of RdRp and thus plays an important role in tight blocking of enzyme active site. Reference drug Remdesivir was used to compare the docking score of antibiotics with RdRp. Docking value exhibited good binding energy (-7.7 up to -8.2 kcal/mol) with RdRp, indicating their potential as a potent RdRp inhibitor. Interaction of CLAM and ERY presented low binding energy (-6.8 and -6.6) with the ACE2 receptor. At the same time, CLAM exhibited a good binding affinity of -6.4 kcal/mol, making it an excellent tool to block the attachment of spike protein to ACE2 receptors. Macrolides not only affected the attachment to ACE2 but also blocked the spike proteins further, consequently inhibiting the internalization in the host cell. Three Alkyl bonds between Arg555, Ala558, and Met542 by CLAM and two Alkyl bonds of Arg624 and Lys621 by ERY plays an important role for RdRp inactivation, that can prevent the rise of newly budded progeny virus. These macrolides interacted with the main protease protein in the pocket responsible for the dimerization and catalytic function of this protein. The interaction occurred with residue Glu166, along with the catalytic residues (Tyr343, and His235) of Endoribonuclease (NSP15) protein. The present study gives three-way options either by blocking S proteins or ACE2 receptor proteins or inhibiting RdRp to counter any effect of COVID-19 by macrolide and could be useful in the treatment of COVID-19 till some better option available.