Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin. Issue 5 (24th March 2022)

• Record Type: Journal Article
• Authors: Sen Gupta, Parth Sarthi; Biswal, Satyaranjan; Panda, Saroj Kumar; Ray, Abhik Kumar; Rana, Malay Kumar
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 5(2022)
• Page Start: 2217
• Page End: 2226
• Publication Date: 2022-03-24
• Subjects: COVID-19 -- molecular target -- ivermectin -- antiviral drug -- molecular dynamics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2020.1839564
• Languages: English
• ISSNs: 0739-1102

Abstract

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. Graphical Abstract: UF0001 Communicated by Ramaswamy H. Sarma