Investigation of Structural Analogues of Azithromycin and Remdesivir for SARS-CoV-2 Mpro: A Computational Approach in Drug Development - Abstract
The Main protease (Mpro) is a vital enzyme of COVID-19 and plays an essential role, making it an attractive antiviral drug target. The antibiotic azithromycin was proven to be effective against influenza, remdesivir is a broad-spectrum antiviral agent that makes activity against various RNA viruses, and lopinavir is the peptidomimetic inhibitor of HIV protease that is recommended for COVID-19. The present computational study has introduced the virtual screening technique for drug repurposing and investigating the structural analogues for azithromycin, remdesivir, and lopinavir. Furthermore, molecular docking is used on active and inactive conformations in Mpro enzyme for comparative study of binding profile between azithromycin, remdesivir, and lopinavir and their analogs erythromycin, sofosbuvir and 3-Amino-N-{4-[2-(2,6-Dimethyl-Phenoxy)- Acetylamino]-3-Hydroxy-1-Isobutyl-5-Phenyl-Pentyl}-Benzamide respectively. The molecular docking between proposed drugs with the native conformation of Mpro demonstrates poor binding because the surface mouth region of the catalytic pocket of Mpro gets a closed form; thus, the drug could not reach the binding pocket. Hence, the findings on ligand-bound or active form signify the following vital information: (i) The antibiotic azithromycin may be used for COVID-19 disease because its structural analog erythromycin is loosely bound at the ligand-binding pocket. (ii) the antiviral remdesivir and its analog sofosbuvir have similar binding energy at the ligand-binding pocket of Mpro. Still,
sofosbuvir has good drug score than remdesivir, and both may be used for COVID-19. (iii) lopinavir has poor binding energy at the active conformation of catalytic pocket rather than its analogue, and also, its drug score is worse than its analogue. We recommend that sofosbuvir is the best structural analogue for remdesivir and may further be considered to use in the preclinical study by replacing remdesivir, the analogues of lopinavir may be further synthesized and require proper experimental and preclinical investigation for the possible treatment of nCOVID-19. Our results were significant and evident in exploring our essential findings with the medical community