Abstract
While an FDA approved drug Ivermectin was reported to dramatically reduce the cell line of SARS-CoV-2 by ∼5000 folds within 48 h, 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 along with Importin-α 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, followed by Importin-α with -9.0 kcal/mol. 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 and Importin-α, with MM/PBSA free energy of -187.3 kJ/mol, almost twice that of Helicase (-94.6 kJ/mol) and even lower than that of Importin-α (-156.7 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.
Keywords: COVID-19; antiviral drug; ivermectin; molecular dynamics; molecular target.
【저자키워드】 COVID-19, Ivermectin, molecular dynamics, antiviral drug, molecular target., 【초록키워드】 Ivermectin, SARS-CoV-2, Antiviral, drug design, molecular dynamics, FDA, RNA dependent RNA polymerase, antiviral drug, free energy, RNA, Helicase, stability, RdRP, target, selectivity, molecular, RNA polymerase, mechanism of action, MM/PBSA, Interaction, In-vitro, identification, lead, the strongest, the cell, followed by, (RdRp, complex, molecular target, cell line, drug complexes, Importin, protein-drug complexes, while, effective, involved, reported, approved, triggered, reduce, reveal, protein-drug complex, 【제목키워드】 Ivermectin, Protein, mechanism, In-vitro, effective,