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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. Communicated by Ramaswamy H. Sarma.

SUBMITTER: Kumar A

PROVIDER: S-EPMC7284142 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Kumar Anuj A Choudhir Gourav G Shukla Sanjeev Kumar SK Sharma Mansi M Tyagi Pankaj P Bhushan Arvind A Rathore Madhu M

Journal of biomolecular structure & dynamics 20200604 10

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<sup>pro</sup>) of COVID-19 by using integrated molecular modeling app ...[more]

PMID: 32448034

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Project description:With the immensely growing outbreaks of hantavirus with still no effective treatment available, there is an urgent need of exploring new computational approaches which will target potential virulent proteins that will eventually reduce its growth. In this study, an envelope glycoprotein, Gn, was targeted. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Inhibitors are herein proposed to negate its action mechanism. On the basis of the scaffolds of favipiravir, a FDA compound already used against hantavirus, a library was designed using a 2D fingerprinting approach. Upon molecular docking analysis, the top four docked compounds-(1) favipiravir (-4.5 kcal/mol), (2) N-hydroxy-3-oxo-3, 4-dihydropyrazine-2-carboxamide (-4.7 kcal/mol), (3) N, 5, 6-trimethyl-2-oxo-1H-pyrazine-3-carboxamide (-4.5 kcal/mol), and (4) 3-propyl-1H-pyrazin-2-one (-3.8)-were prioritized on the basis of the lowest binding energies score. Through molecular docking, the best-categorized compound was subjected to molecular dynamics simulation for a 100-ns time span. Molecular dynamics sheds light on each ligand behavior within the active site. Among the four complexes, only favipiravir and 6320122 compound were found to be stable inside the pocket. This is due to the presence of common rings, pyrazine and carboxamide ring, which make a significant interaction with active key residues Furthermore, the MMPB/GBSA binding free energy analysis calculated for all complexes supported the dynamics results by calculating the most stable values for favipiravir complex (-9.9933 and -8.6951 kcal/mol) and for 6320122 compound complex (-13.8675 and -9.3439 kcal/mol), which demonstrated that the selected compounds have a proper binding affinity with the targeted proteins. The hydrogen bond analysis similarly revealed a strong bonding interaction. The results yielded a strong interaction between the enzyme and the inhibitor throughout the simulation; thus, the inhibitor has the potential to become a lead compound and could be subjected to experimental evaluation to unveil their blockage ability.

Project description:Siddha medicine is one of the oldest medical systems in the world and is believed to have originated more than 10,000 years ago and is prevalent across ancient Tamil land. It is undeniable that inhibitor preferences rise with increasing solubility in water due to the considerations pertaining to the bioavailability and the ease of which unabsorbed residues can be disposed of. In this study, we showed the phytochemical discrimination of Saussurea costus extracted with water at room temperature as a green extraction procedure. A total of 48 compounds were identified using gas chromatography-mass spectrometry (GC-MS). The fatty acids had a high phytochemical abundance at 73.8%, followed by tannins at 8.2%, carbohydrates at 6.9%, terpenoids at 4.3%, carboxylic acids at 2.5%, hydrocarbons at 2.4%, phenolic compounds at 0.2%, and sterols at 1.5%. Of these compounds, 22 were docked on the active side and on the catalytic dyad of His41 and Cys145 of the main protease of SARS-CoV-2 (Mpro). Eight active inhibitors were carbohydrates, five were fatty acids, three were terpenoids, two were carboxylic acids, one was a tannin, one was a phenolic compound, and one was a sterol. The best inhibitors were 4,8,13-Cyclotetradecatriene-1,3-diol, 1,5,9-trimethyl-12-(1-methylethyl), Andrographolide, and delta.4-Androstene-3.beta.,17.beta.-diol, with a binding affinity that ranged from -6.1 kcal/mol to -6.5 kcal/mol. The inhibitory effect of Saussurea costus of SARS-CoV-2 entry into the cell was studied using a pseudovirus with Spike proteins from the D614G variant and the VOC variants Gamma and Delta. Based on the viral cycle of SARS-CoV-2, our results suggest that the Saussurea costus aqueous extract has no virucidal effect and inhibits the virus in the events after cell entry. Furthermore, the biological activity of the aqueous extract was investigated against HSV-1 virus and two bacterial strains, namely Staphylococcus aureus ATCC BAA 1026 and Escherichia coli ATCC 9637. According to this study, an enormous number of water-soluble inhibitors were identified from Saussurea costus against the Mpro, and this is unprecedented as far as we know.

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

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

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