key: cord-0183867-vufygjcc
authors: Sharma, Arun Dev; Kaur, Inderjeet
title: Molecular docking studies on Jensenone from eucalyptus essential oil as a potential inhibitor of COVID 19 corona virus infection
date: 2020-04-01
journal: nan
DOI: nan
sha: 92a4865e560a9dfbedc5e8fa1cfa3d095ed45f92
doc_id: 183867
cord_uid: vufygjcc

COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction. The present in silico study was designed to evaluate the effect of Jensenone, a essential oil component from eucalyptus oil, on Mpro by docking study. In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.The calculated parameters such as binding energy, and binding site similarity indicated effective binding of Jensenone to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/ Jensenone complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions. Therefore, Jensenone may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.

COVID-19 is easily transmissible and it has already been spread worldwide. Symptoms are flu-like and can include fever, muscle and body aches, coughing, and sore throat. Symptoms may appear 5-6 days after infection. As of March 20h, 2020, over 243,000 cases of COVID-19 have been confirmed worldwide, over 10,000 of which have resulted in death. At present, no specific therapies for COVID-19 are available and research regarding the treatment of COVID-19 are infancy. However, the measures that have been implemented remain limited to preventive and supportive therapies, designed to prevent further complications and organ damage [Morales et al., 2020] . Some preliminary studies have investigated potential combinations that include anti malarial drug chlorouinone, and anti-HIV vaccines can be used to treat COVID-19 infections.

A separate investigation performed by Lu (2020) indicated that among 4 tested drugs (nelfinavir, pitavastatin, perampanel, and praziquantel), nelfinavir was identified as the best potential inhibitor against COVID-19.

The main protease (Mpro)/chymotrypsinlike protease (3CLpro) from COVID-19, represents a potential target for the inhibition of CoV replication [Lu, 2020] . It was observed that genome of CoV encodes two proteins ppla and pplb which are involved in spike, membrane, envelop, nucleoprotein, replicase, and polymerase activity of viruses. This function is performed by main protease (Mpro/3CLpro) (Liu and Wang, 2020 [Zakaryan et al., 2017] . Essential oils are highly volatile substances in a mixture of terpenes, oxygenated derivatives and other aromatic compounds. Jensenone is the another component found in eucalyptus oil from all eucalyptus plants (Goodger et al., 2016) . Jensenone is a natural organic compound that is a colorless liquid. It is a cyclic ether and a monoterpenoid. In the present study, we investigated Jensenone as potential inhibitor candidates for COVID-19 Mpro. The findings of the present study will provide other researchers with opportunities to identify the right drug to combat COVID-19.

COVID-19 3CLpro/Mpro structures were obtained from PDB (https://www.rcsb.org/). The native ligand for 3clpro/Mpro structures was Jensenone.

The 3-dimensional (3D) structure of Jensenone was obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/). PubChem is a chemical substance and biological activities repository consisting of three databases, including substance, compound, and bioassay databases.

The docked complex structure output format was submitted into the Protein Interactions Calculator (PIC) webserver ©2020 The author(s). Published by National Press Associates. This is an open access article under CC-BY License (https://creativecommons.org/licenses/by/4.0/), (http://pic.mbu.iisc .ernet.in/) in order to map the interaction of the resulting docked complex. The parameters such as number of hydrogen bonds, number of hydrophobic residues, and number of aromatic and ionic interactions were considered in interpreting the strength of the interaction

The amino acids in the active site of a protein were determined using the Computed Atlas for Surface Topography of Proteins (CASTp) (http://sts.bioe.uic.edu/castp/index.html?2 01l).

The docking study of the compound over COVID-19 Mpro was studied using 1-click docking (https://mcule.com/apps/1-clickdocking/) and swiss doc (http://www.swissdock.ch/ ) softwares. 

Computational and structural biology methods have accelerated the discovery of novel drugs used to treat viral diseases. Corona viruses (CoVs) are a group of viruses that infect animals and humans. CoV infections affect animals in various ways like: respiratory, fever, cold, digestive, and liver systems of humans and animals. It is the main protease (Mpro) found in the CoV associated with the severe acute respiratory syndrome (SARS), which can be accessed in PDB and was suggested to be a potential drug target for 2019-nCov [Lu, 2020) . In many viruses, proteases play essential roles in viral replication; therefore, proteases are often used as protein targets during the development of antiviral therapeutics. In CoV, the Mpro protein is involved in virus proteolytic maturation and has been examined as a potential target protein by inhibiting the cleavage of the viral polyprotein to prevent the spread of infection. The invention of the Mpro/3CLpro protease structure in COVID-19 provides a nice path to identify potential drug candidates to prevent infection. As cited by Liu and Wang (2020), proteases represent key targets for the inhibition virus replication, and the protein sequences of the SARS-CoV Mpro and the 2019-nCoV Mpro are 96% identical, hence host proteases can be used as potential therapeutic targets. We followed the structural biology aspects which focus on the availability and retrieval of a main protease (Mpro) or 3C-like protease (3CLpro) receptor structure from PDB database. The ligand (Jensenone) was docked to main protease (Mpro) or 3C-like protease (3CLpro) using 1-click and swiss dock softwares. Table 1and 2 shows the structure of ligand and amino acids found in the active site pockets of Mpro. in Jensenone compounds are predicted to play roles amino acid residue interactions at the active site of COVID-19 Mpro.

Once we observed that the Jensenone could potentially bind to Mpro/3CLpro protein, the next step was to know the binding mode. Table 4 . These residues may be considered as key or critical and may play a major role in the protein protein-interaction and might inhibit the formation of the betabarrel motif of Mpro/3CLpro. Further studies may help to understand the role of these residues in drug binding mechanism. Structural flexibility is one of the important physical properties that affect protein conformation and function. Whereas high increase in kinetics energy and protein flexibility can disrupt non covalent interactions as in thermal denaturation; a sharp decrease in flexibility can also cause protein denaturation as seen in cold denaturation. Therefore, proteins need an essential amount of flexibility to carry out their native function at physiological conditions. In this context, an inhibitor by binding to a protein can alter its flexibility and decrease its enzymatic activity. Finally, lack of wet-lab validation is a drawback in our research and we expect computational biology analysis and its integration with wet-lab data can be productive in the determination of potential anti-Mpro/3CLpro components. 

Due to non approved drugs at present Currently, COVID-19 has emerged in the human population, in China, and is a potential threat to global health, worldwide.

Currently, the main target for COVID-19 treatment primarily act on the main protease (Mpro). The aim of this study was to examine Jensenone from eucalyptus essential oil that may be used to inhibit the COVID-19 infection pathway. Jensenone has high binding affinity and lowest binding energies. Therefore, we suggested that may Jensenone may represent potential treatment options, and found in medicinal plants that may act as potential inhibitors of COVID-19 Mpro. However, further studies should be conducted for the validation of these compounds using in vitro and in vivo models to pave a way for these compounds in drug discovery.

Published by National Press Associates. This is an open access article under CC-BY License

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Correction: Foliar Essential Oil Glands of Eucalyptus Subgenus Eucalyptus (Myrtacea e) Are a Rich Source of Flavonoids and Related Non-Volatile Constituents

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ADS want to thank management for this support.

The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors Author contributions

ADS: designed the study and prepared manuscript IJK: designed the study and prepared manuscript