PMC:5056895 / 14482-18288 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5056895","sourcedb":"PMC","sourceid":"5056895","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5056895","text":"Virtual screening and validation of docking results\nThe virtual screening technique is an economical, reliable and time saving method for screening large set of lead molecules. In our study, we have used PyRx 0.8 [24] for screening lead molecules against NS3 protein was used to solve the purpose. The NS3 protein of ZIKV was used as receptor to screen 4,121 drug-like compounds (small molecules) based on properties of berberine such as molecular weight of 336.367 g/mol, Xlog p-value of 0.20, net charge of 1, rotatable bonds 2, polar surface area 41Å2, hydrogen donor 0, hydrogen acceptor 5, apolar desolvation 8.91 kcal/mol, and polar desolvation of 8.91 kcal/mol. Further, an approximate range molecular weight ranges from (300 to 400 g/mol); Xlog p (0.10 to 0.50); net charge (–1 to 3); rotatable bonds (1 to 5); polar surface area (20 to 60 Å2); hydrogen donor (0 to 5); hydrogen acceptor (2 to 8); apolar desolvation (5 to 15 kcal/mol); and polar desolvation ranges from (–40 to –10 kcal/mol) was taken to retrieve similar drug compounds from ZINC database. AutoDock Vina [26] in PyRx 0.8 was employed for screening the ligands which generates nine distinct poses of each ligand. Further, based on the hydrogen bond interaction with active site residues of NS3, the docking pose for each ligand was selected.\nTop ten drug like compounds (Table 2) obtained by virtual screening bound to catalytic site of NS3 protein with lowest binding energy were taken as promising candidates for further analysis. All the ligand molecules observed to follow the Lipinski's rule of five (molecular weight not more than 500 Da; hydrogen bond donor not more than 5; hydrogen bond acceptors not more than 10; log p-value not greater than 5). The chemical structure of these ten compounds along with known inhibitor berberine are given in Fig. 3.\nAll the proposed lead molecules were observed to form hydrogen bonds with active site residues of NS3 protein (Fig. 4). The Lead 1 molecule is ZINC53047591(2(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopent an]-4(6H)-one); having molecular weight 456.64218 (g/mol) showed the lowest binding of –7.1 kcal/mol and observed to interact with active site residues of NS3 by forming hydrogen bonds with SER135 and ASN152. The other nine lead molecules are also observed to inhibit NS3 protein with significant lower binding energy as compared to berberine. Thus, the higher binding affinity of selected lead molecules compared to berberine in respective docking complexes proposed that the selected ligands would probably bind more competitively in the active site of NS3 protein (Table 2).\nThe participation of selected lead molecules have very important role to inhibit the NS3 protein through hydrogen bonding interaction with its active site residues justified them as possible inhibitors against the important enzyme of ZIKV. Therefore, the given inhibitors may be demonstrated through biochemical assays.\nIn conclusion, the ZIKV belongs to Flaviviridae family, which is similar to DENV, West Nile virus and yellow fever virus. Currently, there are no specific drugs for prevention and treatment of ZIKV. As, the NS3 protein of this virus perform a central part in the viral life cycle, it is of appreciable interest in designing new potential drug candidate to deal with conquer the challenges of ZIKV infection. A high quality 3D structure of NS3 protein was predicted and validated through computational approach and molecular docking technique was employed to observe the interaction of the existing drugs used against other flavivirus, against ZIKV NS3 protein. Further, for identifying novel inhibitors, high-throughput virtual screening approach was employed in this study, would be of significant in designing new drugs for ZIKV infection.","divisions":[{"label":"Title","span":{"begin":0,"end":51}}],"tracks":[{"project":"2_test","denotations":[{"id":"27729840-25618350-44841875","span":{"begin":214,"end":216},"obj":"25618350"},{"id":"27729840-19499576-44841876","span":{"begin":1081,"end":1083},"obj":"19499576"}],"attributes":[{"subj":"27729840-25618350-44841875","pred":"source","obj":"2_test"},{"subj":"27729840-19499576-44841876","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#c9ec93","default":true}]}]}}