key: cord-0867417-1p1f632p authors: Dubey, Kushagra; Dubey, Raghvendra title: Computation screening of narcissoside a glycosyloxyflavone for potential novel coronavirus 2019 (COVID-19) inhibitor date: 2020-05-18 journal: Biomed J DOI: 10.1016/j.bj.2020.05.002 sha: 3f6eab434979d96b41eb67d957db86c8bbf199fe doc_id: 867417 cord_uid: 1p1f632p OBJECTIVE: The present study demonstrates the potential of flavanoid narcissoside against the novel corona virus (COVID-19) complications using molecular docking studies. METHOD: The computation molecular docking screening was performed using Molegro Virtual Docker software (MVD) with grid resolution of 30 Å. Protein of COVID 19 virus was taken from protein data bank. RESULT: The standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide) identified from the protein inhibitor complex 6W63 from protein data bank was docked with COVID 19 protein 6W63 which showed MolDock score of −156.913, rerank Sore −121.296 and H Bond −5.7369, while the flavanoid narcissoside had showed MolDock score −180.739, Rerank Sore −137.092 and H Bond −18.6771. The narcissoside showed potent inhibitory effect which is greater than standard X77. The result showed that narcissoside have high affinity towards 6W63 as it showed thirteen hydrogen bonds with nine amino acids (Arg 188, Glu 166, His 164, Cys 145 (2 bonds), Asn 14 (2 bonds), Cys 44 (2 bonds), His 41 (2 bonds), Gln 192, Thr 190) while X777 showed four hydrogen bonds with amino acids (Gly 143, Cys 145, Glu 166, Ser 144). CONCLUSION: From computation approach it was concluded that narcissoside is a potent inhibitor of viral COVID 19 protein 6W63. The narcissoside have high affinity and inhibition potential than standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide). The narcissoside predicted as more potent inhibitor which can be further optimize, pharmacologically and clinically evaluated for the treatment of novel coronavirus COVID-19. Q2 An ongoing outbreak of respiratory syndrome caused by a novel coronavirus called as COVID-19 which was reported in Wuhan, China in December 2019 [1e3] .In the following months the infection was spread across the world and is becoming an important causative agent for the fatal disease [4e7] . It is a great global public health concern and extensive measures are taken to reduce transmission of COVID-19 to control the current outbreak. With the emergence of new virus strains, there is a need for the development of the novel and effective antiviral for the treatment of COVID-19. In the present work, an attempt was made using computational approach to identify the potential flavones inhibitors narcissoside that binds to coronavirus for the treatment of COVID-19. Despite of various system of medicine available for the treatment, the recent curiosity is particularly in medicinal plants which have been important sources of new drugs, leads, and new chemical entities [8e11]. Molecular modeling and structure-based drug design has been a promising technique to discover novel inhibitors and has become a famous practice in modern drug discovery. Until the computational drug discovery was adopted, the drugs were identified by chance in a manner of trial and error. Computer-aided drug design helps to facilitate and speed up the drug designing process, which involves a variety of methods to identify novel compounds. Flavonoids are the natural substance widely distributed in grains, fruits, vegetables, leaves, barks, stems, roots and flowers. With more than 4000 variable phenolic structures, flavonoids have been discovered from plant species. Flavonoids are more investigated and are interesting compounds and almost many of them are of pharmacological importance. It has been demonstrated through numerous scientific studies that the flavonoids have antibacterial, anti-angiogenesis, antiinflammatory, antiviral, antiatherosclerotic, antitumor, antithrombogenic, and antifungal activity [12, 13] . The narcissoside, also known as narcissin is an Isorhamnetin-3-O-rutinoside flavonoid that belongs to monomethoxyflavone derivative and has been isolated from number of medicinal plants some are wild plant Peucedanum aucheri Boiss [14] , leaves of Manihot escylenta Crantz (Cassava leaves) [15] , Shoots of Caragana spinosa [16] , flowers of Flos Sophorae Immaturus [17] , plants of Nitaria Genus [18] , leaves of Gynura divaricata [19] , and aerial parts of Atriplex halimus L [20] . The COVID-19 inhibitor N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide reported as inhibitor in binding state with the protein 6w63 in protein data bank and 3-O-Methylquercetin 3-rutinoside ( Fig. 1) were identified from PubChem chemical database. The structures were drawn using Chem3D and energy minimization using the MM2 force field and saved in.mol format. The missing bond orders, charges, bonds, and hybridization states of the structures were assigned using MVD software [21] . The 3D structure of the viral protein was retrieved from the Protein Data Bank (PDB ID: 6W63) and the proteins were prepared by removal of all water molecules, ligand, cofactors and assigning bonds, bond order, hybridization, and charges using MVD software [21] . Piecewise Linear Potential (PLP) algorithm is used for scoring function in the computation screening. MolDock simplex evolution search algorithm with grid resolution 30 A was used to carried out docking process [22] . The cavity were predicted and restricted to three using cavity prediction wizard, the cavity with the large volume was selected as the origin for the binding site. The ligands were docked with viral protein and bestgenerated poses were selected based on the docking scores [23] . The energies are calculated in two scoring function Moldock Score and Rerank Score. MolDock score. E score which is a docking scoring function, defined by the following energy terms: Where E inter is the sum of ligandeprotein interaction energy, ligandewater interaction energy and ligandecofactor interaction energy while E intra is the internal energy of the ligand [24] . The E intra energy includes sum of interactions energies of electronic, H bond, clash, sp2-sp2 hybridization, steric, torsal, torsal (ligand atoms), vanderwaal, soft constraint penalty and E-solvation. Re rank score. In MVD, the rerank score provides an estimation of the interaction strength.This is not measured in chemical units and does not require complex contributions [24] . The results reported in Table 1 The Docking score indicated that the standard X77 showed MolDock score of À156.913, rerank Sore À121.296 and H Bond À5.7369, while the flavanoid narcissoside had showed Mol-Dock score À180.739, Rerank Sore À137.092 and H Bond À18.6771. The narcissoside showed potent inhibitory effect which is greater than standard X77. Many of the patients were infected by exposure to the environment and transmission from person to person. Our present study is aimed to find out the potent inhibitor from natural origin against this corona virus. In our study both the inhibitors has bound the active cavity of protein and showed significant binding with amino acids. The interaction showed that Narcissoside showed high affinity then the standard X77 as Narcissoside showed thirteen hydrogen bonds with nine amino acids (Arg 188, Glu 166, His 164, Cys 145 (2 bonds), Asn 14 (2 bonds), Cys 44 (2 bonds), His 41 (2 bonds), Gln 192, Thr 190) while X77 showed four hydrogen bonds with amino acids (Gly 143, Cys 145, Glu 166, Ser 144) showed in Fig. 2 . It was also observed that the andrews affinity i.e. function group contribution to drug receptor interaction, for the narcissoside is 24.6248 which is 2.5 times more than standard X77 (i.e. 9.161). The outbreak of the pandemic respiratory syndrome caused by a novel coronavirus (COVID-19) requires the attention of global researcher to discover the possible safe and effective medicine to cure the same. In the present work the standard inhibitor X77 and Narcissoside were docked with the protein of novel corona virus COVID-19 6W63. It was observed that the affinity of the Narcissoside was more as compare to standard X77. Narcissoside get fits perfectly at the active site of the 6W63 and showed thirteen hydrogen bonds with nine amino acids in the cavity, while the standard X77 showed only four hydrogen bonds with amino acids. Further research can be performed to identify the safety and efficacy parameters at both preclinical and clinical stages to evaluate the effectiveness of Narcissoside for the treatment of novel coronavirus COVID-19. None. 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