Structural and molecular basis of the interaction mechanism of selected drugs towards multiple targets of SARS-CoV-2 by molecular docking and dynamic simulation studies- deciphering the scope of repurposed drugs

Abstract

The repurposing of FDA approved drugs is presently receiving attention for COVID-19 drug discovery. Previous studies revealed the binding potential of several FDA-approved drugs towards specific targets of SARS-CoV-2; however, limited studies are focused on the structural and molecular basis of interaction of these drugs towards multiple targets of SARS-CoV-2. The present study aimed to predict the binding potential of six FDA drugs towards fifteen protein targets of SARS-CoV-2 and propose the structural and molecular basis of the interaction by molecular docking and dynamic simulation. Based on the literature survey, fifteen potential targets of SARS-CoV-2, and six FDA drugs (Chloroquine, Hydroxychloroquine, Favipiravir, Lopinavir, Remdesivir, and Ritonavir) were selected. The binding potential of individual drug towards the selected targets was predicted by molecular docking in comparison with the binding of the same drugs with their usual targets. The stabilities of the best-docked conformations were confirmed by molecular dynamic simulation and energy calculations. Among the selected drugs, Ritonavir and Lopinavir showed better binding towards the prioritized targets with minimum binding energy (kcal/mol), cluster-RMS, number of interacting residues, and stabilizing forces when compared with the binding of Chloroquine, Favipiravir, and Hydroxychloroquine, later drugs demonstrated better binding when compared to the binding with their usual targets. Remdesvir showed better binding to the prioritized targets in comparison with the binding of Chloroquine, Favipiravir, and Hydroxychloroquine, but showed lesser binding potential when compared to the interaction between Ritonavir and Lopinavir and the prioritized targets. The structural and molecular basis of interactions suggest that the FDA drugs can be repurposed towards multiple targets of SARS-CoV-2, and the present computational models provide insights on the scope of repurposed drugs against COVID-19.

Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism

“…The radar distribution of CQ and HCQ binding affinities towards the allelic variants of ACE2 showed superposition only in four alleles which are rs762890235 (P389H), rs755691167 (K68E), rs1299103394 (K26E), and rs778500138 (E35D) ( Figure 2 ). Recently, it has been reported that CQ and HCQ also interact differently with fifteen protein targets of SARS-CoV-2 using molecular docking and dynamics [ 39 ]. This can interfere with the inhibitory activity of ACE2, which has been previously reported [ 22 ].…”

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

“…These residues can play an important role in stabilizing the PLpro-ligand complexes, as previously reported. [81,83,84] In addition, the rigid docking (considering the cases with the largest negative ΔG and with a suitably good distance from the À SH of Cys111) with the other EbSe metabolites and derivatives demonstrates that the conformers of EbSe-SeGlcA, EbSeO-(S), and EbSe-OH interact predominantly with the carbonyl moiety of the amide bond of the N-phenylbenzamide group, while EbSe-GSH, EbSe-GSH-(R), and EbSe-GSH-(S) interact with the carbonyl of the peptide bond of the GSH moiety (Table S2). EbSeO-(R) and EbSeO 2 showed a Se … SH interactions, whereas EbSe-Me, EbSe-Me-OH, EbSeO-Me-(R), EbSeO-Me-(S), EbSe-Cys, Eb-SeOOH-(R), and EbSeOOH-(S) interacted with the active site of PLpro both via Se … SH and O=C … SH interactions.…”

Network of “drug-target-SARS-CoV-2 Related Genes” Through Integrated Analysis of Pharmacology and Geo Database

“…Identi cation of potential molecular targets is essential for drug repurposing [30][31][32] . Through the construction of molecular docking model between hub host gene and hub compound, it was found that folic acid (FA) and protein ILB, PTGS2, STAT1 were stable binding, and estrogen was stable binding to IL6, IL8.…”