Molecular docking and simulation studies on SARS-CoV-2 M^pro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19

Abstract

The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30 th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 M pro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com ) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 M pro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the M pro cavity and thus having conformational stability. Glutamic acid (Glu166) of M pro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 M pro .

Biflavonoids from Rhus succedanea as probable natural inhibitors against SARS-CoV-2: a molecular docking and molecular dynamics approach

“…N3. Previous computational docking reports and our recent report on Mpro from SARS-CoV-2 demonstrated the interaction of similar key amino acids in the binding cavity (Lakshmi et al., 2020 ; Lokhande et al., 2020b ).…”

“…The computed Prime MM/GBSA energies of the six biflavonoids complexed with SARS-CoV-2 Mpro were described in Table 4 . The stability of the receptor-ligand complex is considered strong when the computed values of binding free energies are more negative (Lokhande et al., 2020b ).…”

“…The computed Prime MM/GBSA energies of the six biflavonoids complexed with SARS-CoV-2 Mpro were described in Table 4. The stability of the receptor-ligand complex is considered strong when the computed values of binding free energies are more negative (Lokhande et al, 2020b). The obtained binding free energies of all reported biflavonoids with SARS-CoV-2 Mpro have the binding free energies less than À70 kcal/mol except biflavonoid like Robustaflavone.…”

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

“…In all the structures, the RMSDs were observed to fluctuate within the range of 0.13–0.32 nm (except the duplicate run of M pro -ZINC000095486008) ( Figure 5 a). A recent study virtually screened FDA-approved antiviral drugs against the M pro and performed 100 ns molecular dynamics simulations of protein–ligand complexes [ 96 ]. The study reported an RMSD range of 1.5 Å (0.15 nm) to 3 Å (0.3 nm), with an average RMSD of 2.25 Å (0.225 nm) for all complexes [ 96 ], consistent with the RMSD range reported ( Figure 6 a) and other studies [ 97 , 98 ].…”

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.…”