Abstract
The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.
Highlights
SARS-CoV-2 is a single-stranded RNA-enveloped virus whose gene fragments consist of structural and non-structural proteins
Top three Main protease (Mpro) inhibitors present in A. indica (Isoquercetin, VEPAOL, and Nimbidiol) showed -9.73, -9.43, and -6.8 kcal/mole binding efficacy at the active site of the Mpro protein
Gly143, Leu27, Thr25, Cys44, Val42, Met49, Cys145, Met165, Arg188, Gln189, Thr190, Pro168, Leu167, Leu141, Ser144, His163, and Phe140 amino acid residues of Mpro protein interacted with Isoquercetin by hydrophobic interaction (Table 3). 10-Hydroxyaloin A showed hydrogen bonding with His41, Leu141, Gly143, and Cys145 residues and interacted with Leu27, Arg188, Thr26, Glu166, Ser144, His164, Asn142, His163, Thr25, Thr45, Cys44, Ser46, Met49, Gln189, Met165 amino acid residues via hydrophobic interaction
Summary
SARS-CoV-2 is a single-stranded RNA-enveloped virus whose gene fragments consist of structural and non-structural proteins. The S1 subunit encompasses a receptor-binding domain (RBD) which interacts with the host receptor protein [such as angiotensinconverting enzyme 2 [ACE2] or TMPRSS2 protein], whereas the S2 subunit negotiates fusion of the virus to the host cellular membrane. These two events are critical to the entry of the viral particle into the host cells. The SARS-CoV-2 Spikeprotein, Mpro, and RdRp proteins are important drugable target to mitigate the viral entry and virulence of the disease. Several preclinical and clinical studies on the chemically synthesized inhibitors of these drugable targets showed significant toxicity and other adverse effects. In the present study we selected two Indian medicinal plants (Azadirachta indica and Aloe vera) based on the rationale reviewed through the literature
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