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. 2022 Apr;29(4):2432-2446.
doi: 10.1016/j.sjbs.2021.12.018. Epub 2021 Dec 13.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies

Mithun Rudrapal  1 , Neelutpal Gogoi  2 , Dipak Chetia  2 , Johra Khan  3   4 , Saeed Banwas  3   4   5 , Bader Alshehri  3   4 , Mohammed A Alaidarous  3   4 , Umesh D Laddha  6 , Shubham J Khairnar  6 , Sanjay G Walode  1
Affiliations

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies

Mithun Rudrapal et al. Saudi J Biol Sci. 2022 Apr.

Abstract

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Keywords: Drug repurposing; Molecular docking; Molecular dynamics; Phytochemicals; Phytomedicine; SARS-CoV-2 infection.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Receptor grid models: (a) 6LU7, (b) 6WX4 and (c): 7BV2.
Fig. 2
Fig. 2
Redocked conformers of receptors: (a) 6LU7, (b) 6WX4, and (c) 7BV2.
Fig. 3
Fig. 3
Different stability related parameters of docked complexes using Mpro obtained from MD analysis: (a) RMSD, (b) RMSF, and (c) ROG.
Fig. 4
Fig. 4
Different stability related parameters of docked complexes using PLpro obtained from MD analysis: (a) RMSD, (b) RMSF, and (c) RO.
Fig. 5
Fig. 5
Different stability related parameters of docked complexes using RdRp obtained from MD analysis: (a) RMSD, (b) RMSF, and (c) ROG.
Fig. 6
Fig. 6
Fluctuations of distances of hydrogen bonds for various docked complexes from MD analysis: (a) Mpro-N3, (b) Mpro-ginsenoside Rg2, (c) PLpro-VIR251, (d) PLpro-saikosaponin A, (e) RdRp-Remdesivir, and (f) RdRp-somniferine.
Fig. 7
Fig. 7
Different non-bond interactions formed for various docked complexes after the simulation period: (a) Mpro-ginsenoside Rg2, (b) Mpro-N3, (c) PLpro-saikosaponin A, (d) PLpro-VIR251, (e) RdRp-somniferine, and (f) RdRp-Remdesivir.
Fig. 8
Fig. 8
Fluctuations of the binding free energy (Delta G) during the simulation period for various complexes: (a) Mpro-ligands, (b) PLpro-ligands, and (c) RdRp-ligands.
Fig. 9
Fig. 9
Structure of some phytochemicals identified as promising protease (Mpro and PLpro) and polymerase (RdRp) inhibitors: (a) Ginsenoside Rg2, (b) Saikosaponin A, (c) Somniferine, (d) Betulinic acid, (e) Soyasapogenol C, (f) Azadirachtin A.
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