Anin-silicoanalysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

Abstract

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing −5.30 kcal/mol and −84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting −6.9 kcal/mol and −66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma

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

“…This stable conformation of IVM at the protein-protein interface suggests that the inhibitory activity of IVM could occur by inhibiting the dimerization of Nsp9 replicase since dimer formation has been related to the enhancement of nucleic acid binding and viral replication (Qiu & Xu, 2020 ). Some of the interactions present in the docked Nsp9-IVM complex (Pro6 and Gly100) were also identified in a previous theoretical study (Azam et al, 2020 ).…”

“…Recently, computational studies employed docking and molecular dynamics (MD) simulations to explore the ability of IVM to inhibit mouse importin-α (PDB entry 5FC8) and several SARS-CoV-2 targets. They found that IVM binds to importin-α with moderate affinity and Nsp9 with the highest affinity among several COVID-19 targets (Azam 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.…”

“…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 ).…”

Targeting SARS-CoV-2 main protease by teicoplanin: A mechanistic insight by docking, MM/GBSA and molecular dynamics simulation

“…In computer-aided drug discovery projects, several docking programs are routinely employed for interpreting the binding mode and the affinity of a ligand relative to a protein. However, the binding energy predicted by docking algorithms cannot be relied and hence, it is imperative to employ post-docking analyses to avoid false negatives and false positives [44] Nowadays, MM-GBSA method is frequently used for predicting the accurate binding energy of a protein-ligand complex and the obtained results can be exploited more rationally in the design of drug candidates. [ 45 , 46 ] Therefore, the top ten poses of SARS CoV-2 main protease–teicoplanin complexes obtained from hundred docking runs in each category were further analysed by MM-GBSA approach for prediction of more accurate binding energy.…”

Misleading clinical evidence and systematic reviews on ivermectin for COVID-19

“…13 17 In a vertiginous search for COVID-19 treatments, Caly et al conducted an in vitro exploration that showed ivermectin's inhibitor role on the replication of the SARS-CoV-2 virus, 17 18 among few other in silico and in vitro results suggesting the same. [19][20][21] Thus, a considerable amount of preprints and protocol records quickly appeared, reporting the clinical efficacy of ivermectin in standard doses for COVID-19. The dissemination of these results caused confusion, and the general population and some clinicians endorsed the use of ivermectin, especially in Latin America.…”