Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α within-vitroeffective drug ivermectin

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.

RETRACTED: Use of ivermectin in the treatment of Covid-19: A pilot trial

“…Ivermectin is a well-known antiparasitic, highly effective against helminthic infestations and with an excellent safety profile. In the past few years, studies have shown that ivermectin also has an antiviral effect on DNA and RNA viral families, preventing the virus from entering cells; promoting inhibition of the transporter complex "nuclear transporter mediated by α / β importin", fundamental to the viral replication process; and binding to RNA-dependent RNA polymerases, also leading to disruption of viral replication [ [1] , [2] , [3] , [4] ].…”

Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets

“…This interaction map appeared more optimized based on the distribution of interactions than predicted by docking procedures ( Figure 1A , supplementary material ). Some of the residues stabilizing IVM and mouse importin-α (Trp184, Asn228, and Trp231) were also observed in a previous theoretical study combining docking and MD simulation to monitor the prevalence of the docked complex (Sen Gupta et al, 2020 ).…”

“…Another recent study employed docking and MD simulations with the molecular mechanics Poisson-Boltzmann surface area (MMGBSA) approach to explore the affinity of IVM with importin-α and several SARS-CoV-2 targets. They identified IVM bound RdRp-RNA and Nsp13 helicase with a higher affinity than importin-α (Sen Gupta et al, 2020 ). Both studies provided critical information that can be used to provide more robust results by employing MD simulations combined with the MMGBSA approach.…”

“…In this contribution, we explore the affinity of IVM for five SARS-Cov2 targets: dimeric 3CL pro , Nsp9 replicase, Nsp13 helicase, RdRp without RNA, and RBD of spike protein, as well as human importin-α, using molecular docking analysis, molecular dynamic MD simulations coupled to the MMGBSA approach, and per-residue decomposition analysis to predict their potential for antiviral treatment of SARS - CoV - 2. From the SARS-CoV-2 targets, Nsp9 replicase, Nsp13 helicase and, RdRp were selected because they had been previously identified as potential targets (Azam et al, 2020 ; Sen Gupta et al, 2020 ). RBD-spike was chosen because it is crucial in recognizing the human angiotensin-converting enzyme-2 (ACE-2) receptor, which makes it indispensable for viral propagation (Chen & Guo, 2020 ; Woo et al, 2010 ).…”

Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities

“…A recent molecular docking study demonstrated that in addition to IMPα, IVM showed high binding affinity to the viral RNA-dependent RNA polymerase (RdRp) complexed with RNA helicase compared to other 10 viral targets included in the analysis ( 43 ). However, it was later shown that IVM does not bind to viral RdRp in both Zika virus (Z.V.)…”