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 (Mpro) 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 Mpro 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 Mpro protein's function and controlling viral replication.

In Silico Identification of Potential Natural Product Inhibitors of Human Proteases Key to SARS-CoV-2 Infection

“…To expedite this search for anti-COVID drugs, several computational studies have used homology modeling or published crystal structures of SARS-CoV-2 proteins, molecular docking and diverse small molecule libraries, to predict potential inhibitors of SARS-CoV-2 proteins including among existing approved drugs for repurposing and natural compounds (see e.g., [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]). In comparison, fewer computational studies [ 16 , 19 ] have focussed on identification of potential inhibitors of host factors.…”

Biomedical Science to Tackle the COVID-19 Pandemic: Current Status and Future Perspectives

“…Computational methods are widely regarded as useful tools in understanding and predicting small molecule active agents in drug development for an efficient targeting and tuned specific effects. The screened drugs and molecules through optimized computational methods might be very useful in fighting COVID-19, as reported recently [ 247 , 248 ]. These results can help in guiding empirical testing during the drug discovery process.…”

“…According to their findings, these molecules have passed the 4 pharmacokinetic steps (Absorption, Distribution, Metabolism, and Excretion) as well as the Lipinski rule of five. These results coming from MD simulations suggest that the three phytochemicals studied could serve as potential inhibitors of SARS-CoV-2 main protease and control the viral replication [ 248 ]. It is important to mention that, to extract reliable predictions from MD simulations, one must consider both sampling configurations produced in the course of time and accurate classical force fields that are used in the equations of motion of the amino acid chains.…”

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation

“…In the drug discovery and development process, the immense therapeutic properties of plants enable researchers to utilize as starting lead molecules for developing drug-like natural molecules. Nowadays, lots of plant data repositories are available for researchers to exploit [31,32]. For example, Kumar et al, 2018 [31] developed an indigenous plant database of Uttarakhand State, India depositing taxonomy, common names, location, medicinal uses, metabolites, interactions, targets, traditional knowledge, etc.…”

“…Various studies already showed that the plant-based study could be an effective place for finding novel leads for COVID-19 drug discovery. Kumar et al [32] screened natural metabolites against the main protease (Mpro) of COVID-19. Qamar et al [33] performed the molecular docking and molecular dynamics simulations study of SARS-CoV-2 3CLpro target using phytochemicals.…”