Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach

Abstract

Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that has been spreading across the globe. The World Health Organization (WHO) declared it as a public health emergency. The treatment of COVID-19 has been hampered due to the lack of effective therapeutic efforts. Main Protease (M^pro) is a key enzyme in the viral replication cycle and its non-specificity to human protease makes it a potential drug target. Cyperus rotundus Linn, which belongs to the Cyperaceae family, is a traditional herbal medicine that has been widely studied for its antiviral properties. In this study, a computational approach was used to screen natural compounds from C. rotundus Linn using BIOVIA Discovery Suite and novel potential molecules against M^pro of SARS-CoV-2 were predicted. Molecular docking was performed using LibDock protocol and selected ligands were further subjected to docking analysis by CDOCKER. The docking scores of the selected ligands were compared with standard antiretroviral drugs such as lopinavir and ritonavir to assess their binding potentials. Interaction pharmacophore analysis was then performed for the compounds exhibiting good binding scores to evaluate their protein-ligand interactions. The selected protein-ligand complexes were subjected to molecular dynamics simulation for 50 ns. Results of binding free energy analysis revealed that two compounds-β-amyrin and stigmasta-5,22-dien-3-ol-exhibited the best binding interactions and stability. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed to understand the pharmacokinetic properties and safety profile of the compounds. The overall results indicate that the phytochemicals from Cyperus rotundus Linn, namely β-amyrin and stigmasta-5,22-dien-3-ol, can be screened as potential inhibitors of SARS-CoV-2 M^pro.

Keywords: Cyperus rotundus Linn; Main protease (M(pro)); Molecular docking and molecular dynamics simulation; Stigmasta-5,22-dien-3-ol; β-amyrin.

Graphical abstract

Fig. 1

Molecular interactions between M^pro and the 12 identified ligands: (a) (E,E)-farnesol, (b) adenosine, (c) β-amyrin, (d) β-amyrin acetate, (e) β-sitosterol, (f) cyperusol, (g) lupeol, (i) oleanolic acid, (j) rosenanolactone, (k) sugetriol-3,9-diacetate, (l) stigmasta-5,22-dien-3-ol, (m) valerenyl acetate.

Fig. 2

Generated receptor-ligand pharmacophore models. cyan colour indicates hydrophobic (H) and magenta colour indicates hydrogen bond donor (HBD). A: M^pro-stigmasta −5,22-dien-3-ol, B:M^pro-β-amyrin, C:M^pro-oleanolic acid, D:M^pro-valrenyl acetate.

Fig. 3

RMSD study plot of screened protein-ligand complexes for 50 ns MD Simulation of M^pro-β-amyrin (Black), M^pro-oleanolic acid (Red), M^pro-stigmasta −5,22-dien-3-ol (Yellow), M^pro-valrenyl acetate (Blue).

Fig. 4

RMSF study plot of screened protein-ligand complexes for 50 ns MD Simulation of M^pro- β-amyrin (Black), M^pro-oleanolic acid (Red), M^pro-stigmasta −5,22-dien-3-ol (Yellow), M^pro-valrenyl acetate (Blue).

Fig. 5

Rg study plot of screened protein-ligand complexes for 50 ns MD Simulation of M^pro- β-amyrin (Black), M^pro-oleanolic acid (Red), M^pro-stigmasta −5,22-dien-3-ol (Yellow), M^pro-valrenyl acetate (Blue).

Fig. 6

SASA study plot of screened protein-ligand complexes for 50 ns MD Simulation of M^pro-β-amyrin (Black), M^pro-oleanolic acid (Red), M^pro-stigmasta −5,22-dien-3-ol (Yellow), M^pro valrenyl acetate (Blue).