The Molecular Docking Study of Interaction of Newly Synthesised Benzamide Appended by Pyrazolone Derivatives as Ligand Molecule With the Target Protien 6lu7 of Novel Corona Virus

The Molecular Docking Study of Interaction of Newly Synthesised Benzamide Appended by Pyrazolone Derivatives as Ligand Molecule With the Target Protien 6lu7 of Novel Corona Virus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Molecular Docking Study of Interaction of Newly Synthesised Benzamide Appended by Pyrazolone Derivatives as Ligand Molecule With the Target Protien 6lu7 of Novel Corona Virus Smt. PAVITHRA V, Dr. SUDHA B S This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3027303/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Plants and bioactive compounds have played an important role in the development of several clinically useful therapeutic agents since time immemorial. The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome corona virus-2 (SARS-CoV-2). As if now there are no approved drugs for the treatment of corona viral disease (COVID-19), although some of the drugs have been tried. The virtual interaction of the COVID-19 main protease in complex with the inhibitor N3 (Research Collaborators for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7), Hence this is chosen as target protein molecule. The newly synthesised compounds of benzamide appended pyrazolones derivatives are made as ligand molecules. The synthesis of these organic ligand molecules is done through four steps using different reagents and different environmental conditions. In this article we have discussed the interaction of our synthesized ligands with the target protein molecule using autodock tools. Firstly, the ligands were prepared using commercial ACD/chemsketch tool in PDB format. Desired protein target 6LU7 is downloaded from Protein Data Bank. Further protein optimization done by removing co-ordinates and hetero atoms, energy minimization of protein is done by swiss PDB viewer 4.1.0. To change the file format open babel 2.4.1 is used. Docking of protein and ligand is done using autodock 4.2 and the results are visualized by pymol and tabulated using the Lamarckian genetic algorithm. After docking comparative study of the binding energies, inhibitory constant and hydrogen bonding of all interactions were discussed and tabulated for the good results. Benzamide pyrazolones protein-ligand interaction molecular docking autodock 4.2 pymol Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Plants and bioactive compounds have played an important role in the development of several clinically useful therapeutic agents since time immemorial. The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As if now there are no approved drugs for the treatment of corona viral disease (COVID-19), although some of the drugs have been tried. The virtual interaction of the COVID-19 main protease in complex with the inhibitor N3 (Research Collaboratory for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7), Hence this is chosen as target protein molecule. The molecular docking approaches are used to model the interaction between a small molecule and a protein at the atomic level, which allow us to characterize the behavior of small molecules in the binding site of target proteins as well as to elucidate fundamental biochemical processes and study of its features. The docking process involves two basic steps they are prediction of the ligand conformation as well as its position and orientation within these sites (usually referred to as pose ) and also assessment of the binding affinity. Pyrazolones are proven to be valuable over wide range of applications in the pharmaceutical industries. The most classic approach to prepare pyrazolones is via the reaction between a β-ketoester, ɑ,β-cyanoester or ɑ,β-unsaturated esters and hydrazine derivatives of alkanes, arenes and heterocycles. Synthesis of benzamide appended heterocycles was initiated, to expand the application of synthesized compounds as the useful drugs. PLAN FOR SYNTHESIS OF LIGANDS Synthesis of substituted benzamides 3a-f was achieved by reacting aminophenol (1) and benzyol chloride (2) in presence of trimethylamine at room temperature for 24hrs, further synthesis of compounds 4a-f is accomplished by reaction of substituted benzamides 3a-f with ethylbromoacetate in presence of potassium carbonate. The obtained acetates 4a-f were reacted with 80% hydrazine hydrate to yield substituted hydrazides 5a-f. These phenyl hydrazides 5a-f were used further for cyclisation with ethylacetoacetate in presence of 20% tetrabutylammonium hydroxide in methanol with ethylene glycol as solvent to achieve substituted N-(4-(2-(5-methyl-3-oxo-2,3-dihydropyrazolyl-1-)2-oxoethoxy)phenyl)benzamide derivatives 6a-f which is our ligand molecule. The structure of synthesized ligands were confirmed by characterization using spectroscopic techniques. Chemicals and solvents used were purchased from Sigma Aldrich and used without further purification unless stated. Melting points were determined in open capillaries on a Buchi oil melting point apparatus and are uncorrected. Reactions were monitored by using thin layer chromatography (TLC) on aluminum sheet precoated with silica gel 60 F254 (0.2mm Merck). Chromatographic spots were visualized by UV light and /or with iodine. For column chromatography, silica gel of 100–200 mesh size was used. 1 H NMR spectra were acquired on a Brucker NRC-IISC instrument, Banglore at ambient temperature at 400 and /or 300 MHz in DMSO-d 6 or CDCL 3 and TMSwas used as an internal reference. 13 C NMR spectra were recorded on a Bruker AMX-400(100 MHz) with complete proton decoupling. Chemical shift are reported in ppm from tetramethylsilane (TMS) with the solvent as the internal refence (CDCl 3 : δ 77.0 ppm or DMSO δ 40.0 ppm). LC-MS was performed on Agilent LCMS system equipped with a BEH C8, 30x4.6mm, 1.7µm column at a flow rate of 1.0ml/min. MOLECULAR DOCKING Molecular docking is a well-established computational technique which predicts the interaction energy between two molecules. This technique is basically incorporates the algorithms like molecular dynamics, fragment search methods and so on.molecular docking also gives the clear idea that what biochemical mechanism is going on between protein and the ligand. In this article we are used to study the interaction of two molecules to fit the best orientation of ligand which would form a complex with overall minimum binding energy. We start with the in-silico generation of ligand and conversion of file format. Futher selection of protein and preparation of protein by optimization of protein and energy minimization. Next using Autodock Vina 4.2 autodock was run to check the interaction and finally analysed by visualization tools and creation of algorithm table. Using commercial ACD/chemsketch tool we have drawn the ligand structure and saved in MDL mol.files and further this file is converted into PDB file format by using open babel 2.4.1 which is a necessary format to run autodock. The selected protein is downloaded from RCSB Protein Data Bank in PDB format. In this article we have selected COVID-19 main protease in complex with the inhibitor N3 (Research Collaborators for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7. Next the protein optimization and energy minimization is done using swiss PDB viewer 4.1.0. by deleting all hetero atoms and co-ordinates. Both ligand and protein molecules are prepared in PDB format which is necessary to run autodock. During docking all water molecules are removed from the protein and polar hydrogen atoms and kollman charges were added to the protein and assigned with AD4 types of atoms. Grid selected around 0.512 value was fixed for every run around the active site of protein that is GLN189 which is obtained by literature survey. The docked files are saved in DLG format by Lamarchian Genetic Algorithm and further it is used for visualization and tabulation of results. The results of molecular docking and the poses of ligand- protein interaction were studied using autock tools for all interactions such as electrostatic forces, hydrogen bonding, torsional effects and so on. Further visualization of the poses of ligand- protein interaction by Pymol. Especially to study the hydrogen bonding interaction of ligand and protein in the selected grid region. The interacted aminoacids were tabulated and studied for further. More the hydrogen bonds more will be the stability of the complex thus all six ligands were studied for their hydrogen bonding interaction with the same protein 6LU7. The selection of grid box size is same for all type of ligands used in the molecular docking studies. Totally ten runs were considered for the best pose of ligand-protein interaction among them the lowest binding energy is considered as the best pose. Further the selected interaction pose of ligand and protein were studied under pymol to get the hydrogen bonding interactions. RESULTS AND DISCUSSION Interaction of ligand-a(N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide) After docking the protein target with each of our ligands, we have observed several information regarding the interactions. Each ligand has slight difference in their interaction type with the selected target protein 6LU7 molecule. According to it for ligand-a and protein 6LU7 interaction we found the least binding energy as -8.90 in the 8th run with the inhibition constant of 301.49 nM and the entropy of the selected grid was found to be 0.41. when the complex in viewed in pymol we found that Ligand-a is having three hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of the three hydrogen bonds are 2.0, 2.4 and 2.5 with the aminoacids GLU166, SER144 and LEU141 respectively. Interaction of ligand-b (4-chloro-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide) ligand-b and protein 6LU7 interaction we found the least binding energy as -8.77 in the 7th run with the inhibition constant of 374.22 nM and the entropy of the selected grid was found to be 0.11. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 2.0 with the amino acids GLY143. Interaction of ligand-c (2,4-dichloro-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide) ligand-c and protein 6LU7 interaction we found the least binding energy as -8.99 in the 3rd run with the inhibition constant of 255.23 nM and the entropy of the selected grid was found to be 0.14. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 2.9 with the amino acids ARG188. Interaction of ligand-d (4-bromo-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide) ligand-d and protein 6LU7 interaction we found the least binding energy as -8.85 in the 7th run with the inhibition constant of 325.66 nM and the entropy of the selected grid was found to be 0.14. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 3.2 with the amino acids GLU166. Interaction of ligand-e (4-methoxy-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide) ligand-e and protein 6LU7 interaction we found the least binding energy as -8.70 in the 3rd run with the inhibition constant of 420.33 nM and the entropy of the selected grid was found to be 0.10. when the complex in viewed in pymol we found that Ligand-a is having two hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that two hydrogen bonds is 2.3 and 4.8 with the amino acids GLY143 and GLN189 respectively. Interaction of ligand-f (N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}-4-nitrobenzamide) ligand-f and protein 6LU7 interaction we found the least binding energy as -9.17 in the 8th run with the inhibition constant of 190.41 nM and the entropy of the selected grid was found to be 0.15. when the complex in viewed in pymol we found that Ligand-a is having three hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that three hydrogen bonds is 2.1, 2.3 and 2.1 with the amino acids GLN192, GLN192 and GLY143 respectively. CONCLUSION More the number of hydrogen bond in the complex more will be the stability and lesser the value of inhibition constant(Ki) more will be the interaction power of the ligand with protein which means a small concentration of ligand can show a good interaction with the protein molecule. When compare the interaction results of all the ligands with same selected protein target molecule, ligand-f is having a good interaction with protein when compare to all ligands because ligand-f is having binding energy as -9.17 in the 8th run with the inhibition constant of 190.41 Nm. Declarations Ethical approval: The data and visualisation images used in this research article are not plagiarised by anywhere. Competing interests: Not applicable Author’s contribution: The whole article is written and data are obtained by author Smt. Pavithra V and the guidance for the research was provided by the corresponding author Dr. Sudha B S. Funding: For this research article no funding is utilised and no funding agencies are involved. Availability of data and materials: The data base and software used for this research article are reproducible and available for universal usage. References Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270–3. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. The Lancet 2020;395:470– Coronavirus disease 2019 https://www.who.int/emergencies/ diseases/novel-coronavirus-2019 Accessed: 2020-04-14. Mcconkey B, Sobolev V, Edelman M. The performance of current methods in ligand-protein docking. Curr Sci;83. Jorgensen WL. The many roles of computation in drug discovery. Science 2004;303:1813–8. Bajorath J. Integration of virtual and high-throughput screening. Nat Rev Drug Discov 2002;1:882–94. Langer T, Hoffmann RD. Virtual screening: an effective tool for lead structure discovery? Curr Pharm Des 2001;7:509–527. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 2004;3:935–949. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature reviews. Drug discovery 2020;19:149–50. Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RTPCR. J Korean Med Sci 2020;35:e79. Lesser, R., and Weiss, R. (1924) Ber. Dtsch. Chem. Ges. 57, 1077–1082 Muller, A., Cadenas, E., Graf, P., and Sies, H. (1984) Biochem. Pharmacol. 33, 3235–3239 Nakamura, Y., Feng, Q., Kumagai, T., Torikai, K., Ohigashi, H., Osawa, T., Noguchi, N., Niki, E., and Uchida, K. (2002) J. Biol. Chem. 277, 2687–2694 Saito, I., Asano, T., Sano, K., Takakura, K., Abe, H., Yoshimoto, T., Kikuchi, H., Ohta, T., and Ishibashi, S. (1998) Neurosurgery 42, 269–277 Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., and Yasuhara, H. (1998) Stroke 29, 12–17 Imai, H., Graham, D. I., Masayasu, H., and Macrae, I. M. (2003) Free Radic. Biol. Med. 34, 56–63 Parnham, M., and Sies, H. (2000) Expert Opin. Investig. Drugs 9, 607–619 Wendel, A., Fausel, M., Safayhi, H., Tiegs, G., and Otter, R. (1984) Biochem. Pharmacol. 33, 3241–3245 Haenen, G. R., De Rooij, B. M., Vermeulen, N. P., and Bast, A. (1990) Mol. Pharmacol. 37, 412–422 Masumoto, H., Kissner, R., Koppenol, W. H., and Sies, H. (1996) FEBS Lett. 398, 179–182 Table Comparative study of interaction of ligand molecule with target protein 6LU7 Name of Ligand Best Run Binding Energy Inhibition Constant Ki Entropy of cluster Number of hydrogen bonds Bond Length Interacted Amino acid Ligand – a 8 -8.90 301.49 nM 0.41 3 2.0 GLU166 2.4 SER144 2.5 LEU141 Ligand – b 7 -8.77 374.22 nM 0.11 1 2.0 GLY143 Ligand – c 3 -8.99 255.23 nM 0.14 1 2.9 ARG188 Ligand – d 7 -8.85 325.66 nM 0.14 1 3.2 GLU166 Ligand – e 3 -8.70 420.33 nM 0.10 2 2.3 GLY143 4.8 GLN189 Ligand – f 8 -9.17 190.41 nM 0.15 3 2.1 GLN192 2.3 GLN192 2.1 GLY143 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3027303","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":207666713,"identity":"ace9810e-1ff0-4ab6-81e1-eccb67e5a8e5","order_by":0,"name":"Smt. PAVITHRA V","email":"","orcid":"","institution":"MMK AND SDM MAHILA MAHA VIDYALAYA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Smt.","middleName":"PAVITHRA","lastName":"V","suffix":""},{"id":207666714,"identity":"c12275a7-6d73-4378-8c7c-b84772787cf4","order_by":1,"name":"Dr. SUDHA B S","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYJCCA4wNUBYPgw2QZGw8QFDLQYSWNJCWBoJaGJC0HIYYgk+1OfsZw8Mfd9yTNzi/+JjEm5rzdmvbDwNtqbGJxqXFsifH4MDBM8WGG248S5Occ+x28rYziUAtx9JyG3BoMTiQlnDgYFsC48wZZ8xu87DdTjY7ANTC2HAYt5bzz8Ba7CFa/p1LNjv/kICWG8kHQFoS+/l7zG7zth2wM7tBwBbLGY8PHDjblpDcL8GW/nNuX3KC2Q2gLQl4/GLOn9j8obItwbaN//Bhgzff7OzNzqc/fPChxga3w+AsiQQwlQhWmYBDOaoW/gNgyh6P4lEwCkbBKBihAABHInDyJS/0tQAAAABJRU5ErkJggg==","orcid":"","institution":"Yuvaraja's college","correspondingAuthor":true,"submittingAuthor":false,"prefix":"Dr.","firstName":"SUDHA","middleName":"B","lastName":"S","suffix":""}],"badges":[],"createdAt":"2023-06-06 05:44:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3027303/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3027303/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":38309705,"identity":"746ebc90-0f19-48ae-8f97-d306d5853f59","added_by":"auto","created_at":"2023-06-09 18:50:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":451388,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSCHEME FOR SYNTHESIS OF LIGAND MOLECULES\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/465806a7198f1d308fbcdb93.jpg"},{"id":38309350,"identity":"c33a4334-1cc7-4d2a-95a0-42b6c5307e11","added_by":"auto","created_at":"2023-06-09 18:42:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":275783,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStructure of benzamide appended by pyrazlones acting as ligands\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/571f3e2958e630f258c6fbf8.jpg"},{"id":38309352,"identity":"5c85d708-f8d6-4e15-8874-825ffecd2efd","added_by":"auto","created_at":"2023-06-09 18:42:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":938290,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMolecular interaction of ligands with molecules\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/d331fee09fd9a411b4feb762.jpg"},{"id":38309353,"identity":"0da5e641-c784-443d-8a81-b8fc7cec03b9","added_by":"auto","created_at":"2023-06-09 18:42:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":883968,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVisualization of protein-ligand interaction in terms of hydrogen bonding\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/7418362f8bb43ec13b88d2ac.jpg"},{"id":38309354,"identity":"3ff8a2e6-8682-48fd-b004-3602a62a1aaf","added_by":"auto","created_at":"2023-06-09 18:42:46","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":905652,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePymol viewer of hydrogen bondings in the protein-ligand complex\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/dfdb65d16b00d2382ffbfd40.png"},{"id":38309706,"identity":"0af772cf-ed9b-49f1-9055-645bda67bd9a","added_by":"auto","created_at":"2023-06-09 18:50:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1116990,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3027303/v1/1384d8e2-9dc2-4786-ac79-9516cb4b9a74.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eThe Molecular Docking Study of Interaction of Newly Synthesised Benzamide Appended by Pyrazolone Derivatives as Ligand Molecule With the Target Protien 6lu7 of Novel Corona Virus\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePlants and bioactive compounds have played an important role in the development of several clinically useful therapeutic agents since time immemorial. The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As if now there are no approved drugs for the treatment of corona viral disease (COVID-19), although some of the drugs have been tried. The virtual interaction of the COVID-19 main protease in complex with the inhibitor N3 (Research Collaboratory for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7), Hence this is chosen as target protein molecule.\u003c/p\u003e \u003cp\u003eThe molecular docking approaches are used to model the interaction between a small molecule and a protein at the atomic level, which allow us to characterize the behavior of small molecules in the binding site of target proteins as well as to elucidate fundamental biochemical processes and study of its features. The docking process involves two basic steps they are prediction of the ligand conformation as well as its position and orientation within these sites (usually referred to as \u003cem\u003epose\u003c/em\u003e) and also assessment of the binding affinity.\u003c/p\u003e \u003cp\u003ePyrazolones are proven to be valuable over wide range of applications in the pharmaceutical industries. The most classic approach to prepare pyrazolones is via the reaction between a β-ketoester, ɑ,β-cyanoester or ɑ,β-unsaturated esters and hydrazine derivatives of alkanes, arenes and heterocycles. Synthesis of benzamide appended heterocycles was initiated, to expand the application of synthesized compounds as the useful drugs.\u003c/p\u003e"},{"header":"PLAN FOR SYNTHESIS OF LIGANDS","content":"\u003cp\u003eSynthesis of substituted benzamides 3a-f was achieved by reacting aminophenol (1) and benzyol chloride (2) in presence of trimethylamine at room temperature for 24hrs, further synthesis of compounds 4a-f is accomplished by reaction of substituted benzamides 3a-f with ethylbromoacetate in presence of potassium carbonate. The obtained acetates 4a-f were reacted with 80% hydrazine hydrate to yield substituted hydrazides 5a-f. These phenyl hydrazides 5a-f were used further for cyclisation with ethylacetoacetate in presence of 20% tetrabutylammonium hydroxide in methanol with ethylene glycol as solvent to achieve substituted N-(4-(2-(5-methyl-3-oxo-2,3-dihydropyrazolyl-1-)2-oxoethoxy)phenyl)benzamide derivatives 6a-f which is our ligand molecule. The structure of synthesized ligands were confirmed by characterization using spectroscopic techniques.\u003c/p\u003e\n\u003cp\u003eChemicals and solvents used were purchased from Sigma Aldrich and used without further purification unless stated. Melting points were determined in open capillaries on a Buchi oil melting point apparatus and are uncorrected. Reactions were monitored by using thin layer chromatography (TLC) on aluminum sheet precoated with silica gel 60 F254 (0.2mm Merck). Chromatographic spots were visualized by UV light and /or with iodine. For column chromatography, silica gel of 100\u0026ndash;200 mesh size was used. \u003csup\u003e1\u003c/sup\u003eH NMR spectra were acquired on a Brucker NRC-IISC instrument, Banglore at ambient temperature at 400 and /or 300 MHz in DMSO-d\u003csub\u003e6\u003c/sub\u003e or CDCL\u003csub\u003e3\u003c/sub\u003e and TMSwas used as an internal reference. \u003csup\u003e13\u003c/sup\u003eC NMR spectra were recorded on a Bruker AMX-400(100 MHz) with complete proton decoupling. Chemical shift are reported in ppm from tetramethylsilane (TMS) with the solvent as the internal refence (CDCl\u003csub\u003e3\u003c/sub\u003e: \u0026delta; 77.0 ppm or DMSO \u0026delta; 40.0 ppm). LC-MS was performed on Agilent LCMS system equipped with a BEH C8, 30x4.6mm, 1.7\u0026micro;m column at a flow rate of 1.0ml/min.\u003c/p\u003e"},{"header":"MOLECULAR DOCKING","content":"\u003cp\u003eMolecular docking is a well-established computational technique which predicts the interaction energy between two molecules. This technique is basically incorporates the algorithms like molecular dynamics, fragment search methods and so on.molecular docking also gives the clear idea that what biochemical mechanism is going on between protein and the ligand. In this article we are used to study the interaction of two molecules to fit the best orientation of ligand which would form a complex with overall minimum binding energy. We start with the in-silico generation of ligand and conversion of file format. Futher selection of protein and preparation of protein by optimization of protein and energy minimization. Next using Autodock Vina 4.2 autodock was run to check the interaction and finally analysed by visualization tools and creation of algorithm table.\u003c/p\u003e\n\u003cp\u003eUsing commercial ACD/chemsketch tool we have drawn the ligand structure and saved in MDL mol.files and further this file is converted into PDB file format by using open babel 2.4.1 which is a necessary format to run autodock. The selected protein is downloaded from RCSB Protein Data Bank in PDB format. In this article we have selected COVID-19 main protease in complex with the inhibitor N3 (Research Collaborators for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7. Next the protein optimization and energy minimization is done using swiss PDB viewer 4.1.0. by deleting all hetero atoms and co-ordinates.\u003c/p\u003e\n\u003cp\u003eBoth ligand and protein molecules are prepared in PDB format which is necessary to run autodock. During docking all water molecules are removed from the protein and polar hydrogen atoms and kollman charges were added to the protein and assigned with AD4 types of atoms. Grid selected around 0.512 value was fixed for every run around the active site of protein that is GLN189 which is obtained by literature survey. The docked files are saved in DLG format by Lamarchian Genetic Algorithm and further it is used for visualization and tabulation of results.\u003c/p\u003e\n\u003cp\u003eThe results of molecular docking and the poses of ligand- protein interaction were studied using autock tools for all interactions such as electrostatic forces, hydrogen bonding, torsional effects and so on.\u003c/p\u003e\n\u003cp\u003eFurther visualization of the poses of ligand- protein interaction by Pymol. Especially to study the hydrogen bonding interaction of ligand and protein in the selected grid region. The interacted aminoacids were tabulated and studied for further.\u003c/p\u003e\n\u003cp\u003eMore the hydrogen bonds more will be the stability of the complex thus all six ligands were studied for their hydrogen bonding interaction with the same protein 6LU7. The selection of grid box size is same for all type of ligands used in the molecular docking studies. Totally ten runs were considered for the best pose of ligand-protein interaction among them the lowest binding energy is considered as the best pose. Further the selected interaction pose of ligand and protein were studied under pymol to get the hydrogen bonding interactions.\u003c/p\u003e"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003eInteraction of ligand-a(N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide)\u003c/p\u003e \u003cp\u003eAfter docking the protein target with each of our ligands, we have observed several information regarding the interactions. Each ligand has slight difference in their interaction type with the selected target protein 6LU7 molecule. According to it for ligand-a and protein 6LU7 interaction we found the least binding energy as -8.90 in the 8th run with the inhibition constant of 301.49 nM and the entropy of the selected grid was found to be 0.41. when the complex in viewed in pymol we found that Ligand-a is having three hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of the three hydrogen bonds are 2.0, 2.4 and 2.5 with the aminoacids GLU166, SER144 and LEU141 respectively.\u003c/p\u003e \u003cp\u003eInteraction of ligand-b (4-chloro-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide)\u003c/p\u003e \u003cp\u003eligand-b and protein 6LU7 interaction we found the least binding energy as -8.77 in the 7th run with the inhibition constant of 374.22 nM and the entropy of the selected grid was found to be 0.11. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 2.0 with the amino acids GLY143.\u003c/p\u003e \u003cp\u003eInteraction of ligand-c (2,4-dichloro-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide)\u003c/p\u003e \u003cp\u003eligand-c and protein 6LU7 interaction we found the least binding energy as -8.99 in the 3rd run with the inhibition constant of 255.23 nM and the entropy of the selected grid was found to be 0.14. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 2.9 with the amino acids ARG188.\u003c/p\u003e \u003cp\u003eInteraction of ligand-d (4-bromo-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide)\u003c/p\u003e \u003cp\u003eligand-d and protein 6LU7 interaction we found the least binding energy as -8.85 in the 7th run with the inhibition constant of 325.66 nM and the entropy of the selected grid was found to be 0.14. when the complex in viewed in pymol we found that Ligand-a is having one hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that one hydrogen bonds is 3.2 with the amino acids GLU166.\u003c/p\u003e \u003cp\u003eInteraction of ligand-e (4-methoxy-N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}benzamide)\u003c/p\u003e \u003cp\u003eligand-e and protein 6LU7 interaction we found the least binding energy as -8.70 in the 3rd run with the inhibition constant of 420.33 nM and the entropy of the selected grid was found to be 0.10. when the complex in viewed in pymol we found that Ligand-a is having two hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that two hydrogen bonds is 2.3 and 4.8 with the amino acids GLY143 and GLN189 respectively.\u003c/p\u003e \u003cp\u003eInteraction of ligand-f (N-{4-[2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy]phenyl}-4-nitrobenzamide)\u003c/p\u003e \u003cp\u003eligand-f and protein 6LU7 interaction we found the least binding energy as -9.17 in the 8th run with the inhibition constant of 190.41 nM and the entropy of the selected grid was found to be 0.15. when the complex in viewed in pymol we found that Ligand-a is having three hydrogen bonds with the target protein molecule 6LU7 with the selected grid box. The bond length of that three hydrogen bonds is 2.1, 2.3 and 2.1 with the amino acids GLN192, GLN192 and GLY143 respectively.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eMore the number of hydrogen bond in the complex more will be the stability and lesser the value of inhibition constant(Ki) more will be the interaction power of the ligand with protein which means a small concentration of ligand can show a good interaction with the protein molecule. When compare the interaction results of all the ligands with same selected protein target molecule, ligand-f is having a good interaction with protein when compare to all ligands because ligand-f is having binding energy as -9.17 in the 8th run with the inhibition constant of 190.41 Nm.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval:\u0026nbsp;\u003c/strong\u003eThe data and visualisation images used in this research article are not plagiarised by anywhere.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution:\u0026nbsp;\u003c/strong\u003eThe whole article is written and data are obtained by author Smt. Pavithra V and the guidance for the research was provided by the corresponding author Dr. Sudha B S.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eFor this research article no funding is utilised and no funding agencies are involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe data base and software used for this research article are reproducible and available for universal usage.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eWang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. The Lancet 2020;395:470\u0026ndash;\u003c/li\u003e\n\u003cli\u003eCoronavirus disease 2019 https://www.who.int/emergencies/ diseases/novel-coronavirus-2019 Accessed: 2020-04-14.\u003c/li\u003e\n\u003cli\u003eMcconkey B, Sobolev V, Edelman M. The performance of current methods in ligand-protein docking. Curr Sci;83.\u003c/li\u003e\n\u003cli\u003eJorgensen WL. The many roles of computation in drug discovery. Science 2004;303:1813\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eBajorath J. Integration of virtual and high-throughput screening. Nat Rev Drug Discov 2002;1:882\u0026ndash;94.\u003c/li\u003e\n\u003cli\u003eLanger T, Hoffmann RD. Virtual screening: an effective tool for lead structure discovery? Curr Pharm Des 2001;7:509\u0026ndash;527.\u003c/li\u003e\n\u003cli\u003eKitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 2004;3:935\u0026ndash;949.\u003c/li\u003e\n\u003cli\u003eLi G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature reviews. Drug discovery 2020;19:149\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eLim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RTPCR. J Korean Med Sci 2020;35:e79. \u003c/li\u003e\n\u003cli\u003eLesser, R., and Weiss, R. (1924) Ber. Dtsch. Chem. Ges. 57, 1077\u0026ndash;1082\u003c/li\u003e\n\u003cli\u003eMuller, A., Cadenas, E., Graf, P., and Sies, H. (1984) Biochem. Pharmacol. 33, 3235\u0026ndash;3239\u003c/li\u003e\n\u003cli\u003eNakamura, Y., Feng, Q., Kumagai, T., Torikai, K., Ohigashi, H., Osawa, T., Noguchi, N., Niki, E., and Uchida, K. (2002) J. Biol. Chem. 277, 2687\u0026ndash;2694\u003c/li\u003e\n\u003cli\u003eSaito, I., Asano, T., Sano, K., Takakura, K., Abe, H., Yoshimoto, T., Kikuchi, H., Ohta, T., and Ishibashi, S. (1998) Neurosurgery 42, 269\u0026ndash;277\u003c/li\u003e\n\u003cli\u003eYamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., and Yasuhara, H. (1998) Stroke 29, 12\u0026ndash;17\u003c/li\u003e\n\u003cli\u003eImai, H., Graham, D. I., Masayasu, H., and Macrae, I. M. (2003) Free Radic. Biol. Med. 34, 56\u0026ndash;63\u003c/li\u003e\n\u003cli\u003eParnham, M., and Sies, H. (2000) Expert Opin. Investig. Drugs 9, 607\u0026ndash;619\u003c/li\u003e\n\u003cli\u003eWendel, A., Fausel, M., Safayhi, H., Tiegs, G., and Otter, R. (1984) Biochem. Pharmacol. 33, 3241\u0026ndash;3245\u003c/li\u003e\n\u003cli\u003eHaenen, G. R., De Rooij, B. M., Vermeulen, N. P., and Bast, A. (1990) Mol. Pharmacol. 37, 412\u0026ndash;422\u003c/li\u003e\n\u003cli\u003eMasumoto, H., Kissner, R., Koppenol, W. H., and Sies, H. (1996) FEBS Lett. 398, 179\u0026ndash;182\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eComparative study of interaction of ligand molecule with target protein 6LU7\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003e\u003cstrong\u003eName of Ligand\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest Run\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"78\"\u003e\n \u003cp\u003e\u003cstrong\u003eBinding Energy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"118\"\u003e\n \u003cp\u003e\u003cstrong\u003eInhibition Constant Ki\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003e\u003cstrong\u003eEntropy of cluster\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"103\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of hydrogen bonds\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e\u003cstrong\u003eBond Length\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003e\u003cstrong\u003eInteracted Amino acid\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"61\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"78\"\u003e\n \u003cp\u003e-8.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"118\"\u003e\n \u003cp\u003e301.49 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"102\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" width=\"103\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eGLU166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eSER144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eLEU141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"78\"\u003e\n \u003cp\u003e-8.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"118\"\u003e\n \u003cp\u003e374.22 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"103\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eGLY143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"78\"\u003e\n \u003cp\u003e-8.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"118\"\u003e\n \u003cp\u003e255.23 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"103\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eARG188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"78\"\u003e\n \u003cp\u003e-8.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"118\"\u003e\n \u003cp\u003e325.66 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"102\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"103\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eGLU166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"61\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"78\"\u003e\n \u003cp\u003e-8.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"118\"\u003e\n \u003cp\u003e420.33 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"102\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"103\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eGLY143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"84\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"121\"\u003e\n \u003cp\u003eGLN189\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"102\"\u003e\n \u003cp\u003eLigand \u0026ndash; 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The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome corona virus-2 (SARS-CoV-2). As if now there are no approved drugs for the treatment of corona viral disease (COVID-19), although some of the drugs have been tried. The virtual interaction of the COVID-19 main protease in complex with the inhibitor N3 (Research Collaborators for Structural Bioinformatics Protein Data Bank [PDB] ID: 6LU7), Hence this is chosen as target protein molecule. The newly synthesised compounds of benzamide appended pyrazolones derivatives are made as ligand molecules. The synthesis of these organic ligand molecules is done through four steps using different reagents and different environmental conditions. In this article we have discussed the interaction of our synthesized ligands with the target protein molecule using autodock tools. Firstly, the ligands were prepared using commercial ACD/chemsketch tool in PDB format. Desired protein target 6LU7 is downloaded from Protein Data Bank. Further protein optimization done by removing co-ordinates and hetero atoms, energy minimization of protein is done by swiss PDB viewer 4.1.0. To change the file format open babel 2.4.1 is used. Docking of protein and ligand is done using autodock 4.2 and the results are visualized by pymol and tabulated using the Lamarckian genetic algorithm. After docking comparative study of the binding energies, inhibitory constant and hydrogen bonding of all interactions were discussed and tabulated for the good results.\u003c/p\u003e","manuscriptTitle":"The Molecular Docking Study of Interaction of Newly Synthesised Benzamide Appended by Pyrazolone Derivatives as Ligand Molecule With the Target Protien 6lu7 of Novel Corona Virus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-09 18:42:41","doi":"10.21203/rs.3.rs-3027303/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7058d63d-88b2-466d-a1b2-c5fd03bf568e","owner":[],"postedDate":"June 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-06T08:14:11+00:00","versionOfRecord":[],"versionCreatedAt":"2023-06-09 18:42:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3027303","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3027303","identity":"rs-3027303","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}