Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel corona virus that causes corona virus disease 2019 (COVID-19). The COVID-19 rapidly spread across the nations with high mortality rate even as very little is known to contain the virus at present. In the current study, we report novel natural metabolites namely, ursolic acid, carvacrol and oleanolic acid as the potential inhibitors against main protease (M pro) of COVID-19 by using integrated molecular modeling approaches. From a combination of molecular docking and molecular dynamic (MD) simulations, we found three ligands bound to protease during 50 ns of MD simulations. Furthermore, the molecular mechanic/generalized/ Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations showed that these chemical molecules have stable and favourable energies causing strong binding with binding site of M pro protein. All these three molecules, namely, ursolic acid, carvacrol and oleanolic acid, have passed the ADME (Absorption, Distribution, Metabolism, and Excretion) property as well as Lipinski's rule of five. The study provides a basic foundation and suggests that the three phytochemicals, viz. ursolic acid, carvacrol and oleanolic acid could serve as potential inhibitors in regulating the M pro protein's function and controlling viral replication.

Natural compounds as potential inhibitors of novel coronavirus (COVID-19) main protease: An in silico study

“…3.6 Binding free energy calculation: In recent reports, it has been demonstrated that 100-200 snapshots are enough to calculate the binding free energies (Khan et al, 2020) (Kumar et al, 2020) (Sarma et al, 2020). The free binding energy results showed that as compare to other molecules Amento avens has maximum binding energy -240.434±17.602-180.787 kJ/mol whereas Guggulsterone has lower binding energy -121.708±12.423 kJ/mol (Table 5).…”

“…MD simulation studies were carried out to nd out the stability and exibility of the natural compounds-M pro complexes on 50ns. The method used for the MD simulations of natural compounds-M pro complexes remains same as earlier described in recent studies (Gajula et al, 2016;Jee et al, 2018;Kumar et al, 2020). All simulations of representative natural compounds-M pro complexes were conducted with the fruitful utilization of GROMOS96 43a1 force eld available in GROMACS 5.1.4 suite (Van Der Spoel et al, 2005).…”

“…Coronavirus disease (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which primarily affects the lungs and shows certain types of pneumonia-like symptoms (Huang et al, 2020;Kumar et al, 2020). SARS-CoV-2 is a novel strain of coronavirus, rst time emerged in December 2019, during an outbreak in Wuhan, China, and subsequently expanded to all over the world in a very short period of time (World Health Organization, 2020; Hendaus, 2020).…”

In silico investigation of phytoconstituents from Indian medicinal herb ‘Tinospora cordifolia (giloy)’ against SARS-CoV-2 (COVID-19) by molecular dynamics approach

“…The steepest descent algorithm has been used for energy minimization of the system with varying time (ps) for 500,000 iteration steps. For reducing the steric clashes, the applied algorithm has a cutoff up to 1000 kJmol À1 (Anuj et al, 2020). The MD simulation has started with the minimization of the system.…”

“…After virtual screening, we have evaluated their potential inhibition properties against CoV-2 main protease by the mechanism of molecular docking. After studying proper binding affinity of proposed drugs against the target receptor by the Molecular docking, finally we have verified the drug inhibition with target receptor by different interaction energies like hydrogen bonding, hydrophobic, coulombic etc by MD simulation approach to validate the applicability of proposed drug molecule as suggested by Anuj et al (2020). In vivo estimation of drug molecules is time consuming and expensive so to deal with the present COVID crisis, in silico methods have become inevitable as we need an urgent solution of SARS-CoV-2 infection.…”