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

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 NCsite 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 RdRwith RNA has better structural stability than the Helicase NCsite, with MMBSA free energy of -135 2 kJ/mol, almost twice that of Helicase (-76 6 kJ/mol) The selectivity of Ivermectin to RdRis triggered by a cooperative interaction of RNA-RdRby 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