<p>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 NCB site 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 RdRp with RNA has better structural stability than the Helicase NCB site, with MM/PBSA free energy of -135.2 kJ/mol, almost twice that of Helicase (-76.6 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. </p>

<p>Due to the current pandemic nature, severity, and rapid spread of COVID-19, there is eminent need to identify potential therapeutics to inhibit the novel coronavirus. In the quest, scientists from the USA had reported that the use of Famotidine in patients was associated with improved clinical outcomes and a reduced risk of intubation or death from COVID-19. However, the exact mode of action, the binding mechanism, and precise <a>COVID-19 </a>molecular target with which Famotidine interacts are yet to be ascertained. Here, 12 different COVID-19 protein targets have been screened against Famotidine employing molecular docking and molecular dynamics simulation. This reveals, among all the targets, the Papain-like protease (PLpro) as the potential target having the strongest affinity to Famotidine estimated to be of -7.9 kcal/mol with three hydrogen bonds. Tyrosine residue in the 268^th position in the binding site seems to be very crucial for the stability of the PLpro-Famotidine complex, giving rise to multiple interactions such as hydrogen bonding as well as π-Sulfur. While the post-molecular dynamics (MD) analyses such as the root-mean-square deviation (RMSD) and fluctuation (RMSF), the radius of gyration (R_g), and the principal component analysis (PCA) affirm the stability of the complex providing an insight into the binding mechanism, the identification of a valid target PLpro of SARS-COV-2 for Famotidine would help understand its action, further development, and experimental exploration.</p>

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<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>