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Binding Mechanism and Structural Insights into the Identified Protein Target of Covid-19 with In-Vitro Effective Drug Ivermectin

preprint
submitted on 11.06.2020 and posted on 12.06.2020 by Parth Sarthi Sen Gupta, Satyaranjan Biswal, Saroj Kumar Panda, Abhik Kumar Ray, Malay Kumar Rana

While an FDA approved drug Ivermectin was reported to dramatically reduce the cell line of SARS-CoV-2 by ~5000 folds within 48 hours, the precise mechanism of action and the COVID-19 molecular target involved in interaction with this in-vitro effective drug are unknown yet. Among 12 different COVID-19 targets studied here, the RNA dependent RNA polymerase (RdRp) with RNA and Helicase NCB site show the strongest affinity to Ivermectin amounting -10.4 kcal/mol and -9.6 kcal/mol, respectively. Molecular dynamics of corresponding protein-drug complexes reveals that the drug bound state of RdRp with RNA has better structural stability than the Helicase NCB site, with MM/PBSA free energy of -135.2 kJ/mol, almost twice that of Helicase (-76.6 kJ/mol). The selectivity of Ivermectin to RdRp is triggered by a cooperative interaction of RNA-RdRp by ternary complex formation. Identification of the target and its interaction profile with Ivermectin can lead to more powerful drug designs for COVID-19 and experimental exploration.

Funding

None

History

Email Address of Submitting Author

mrana@iiserbpr.ac.in

Institution

Indian Institute of Science Education and Research Berhampur

Country

India

ORCID For Submitting Author

0000-0002-1713-8220

Declaration of Conflict of Interest

The authors report no conflicts of interest.

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