title: Pharmacoinformatics approach for investigation of alternative potential hepatitis C virus nonstructural protein 5B inhibitors.
abstract: Hepatitis C virus (HCV) is one of the major viruses affecting the world today. It is a highly variable virus, having a rapid reproduction and evolution rate. The variability of genomes is due to hasty replication catalyzed by nonstructural protein 5B (NS5B) which is also a potential target site for the development of anti-HCV agents. Recently, the US Food and Drug Administration approved sofosbuvir as a novel oral NS5B inhibitor for the treatment of HCV. Unfortunately, it is much highlighted for its pricing issues. Hence, there is an urgent need to scrutinize alternate therapies against HCV that are available at affordable price and do not have associated side effects. Such a need is crucial especially in underdeveloped countries. The search for various new bioactive compounds from plants is a key part of pharmaceutical research. In the current study, we applied a pharmacoinformatics-based approach for the identification of active plant-derived compounds against NS5B. The results were compared to docking results of sofosbuvir. The lead compounds with high-binding ligands were further analyzed for pharmacokinetic and pharmacodynamic parameters based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. The results showed the potential alternative lead compounds that can be developed into commercial drugs having high binding energy and promising ADMET properties.
authors.affiliation: Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan.
authors.forename: Muhammad Usman
authors.initials: MU
authors.lastname: Mirza
authors.affiliation: Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Science and Technology, Islamabad, Pakistan.
authors.forename: Noor-Ul-Huda
authors.initials: NU
authors.lastname: Ghori
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan.
authors.forename: Nazia
authors.initials: N
authors.lastname: Ikram
authors.affiliation: Centre for Excellence in Molecular Biology (CEMB), The University of Punjab, Lahore, Pakistan.
authors.forename: Abdur Rehman
authors.initials: AR
authors.lastname: Adil
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore, Pakistan.
authors.forename: Sadia
authors.initials: S
authors.lastname: Manzoor
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D008024:Ligands; D008490:Medical Informatics; D062105:Molecular Docking Simulation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: ADMET; AutoDock Vina; NS5B inhibitors; hepatitis C; molecular docking; phytochemicals; sofosbuvir
references.citation: Infect Drug Resist. 2014 Mar 05;7:41-56
references.pmid: 24623983
references.citation: Prog Drug Res. 2008;65:211, 213-49
references.pmid: 18084917
references.citation: Pharm Res. 1996 Aug;13(8):1133-44
references.pmid: 8865302
references.citation: Proc Soc Exp Biol Med. 1974 Dec;147(3):813-5
references.pmid: 4445171
references.citation: J Chem Inf Comput Sci. 2003 Jul-Aug;43(4):1308-15
references.pmid: 12870924
references.citation: J Med Chem. 2011 Jan 13;54(1):289-301
references.pmid: 21141896
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W116-8
references.pmid: 16844972
references.citation: Nat Rev Drug Discov. 2004 Nov;3(11):935-49
references.pmid: 15520816
references.citation: J Chem Inf Model. 2012 Nov 26;52(11):3099-105
references.pmid: 23092397
references.citation: NeuroRx. 2005 Oct;2(4):554-71
references.pmid: 16489365
references.citation: Hepatology. 2002 Nov;36(5 Suppl 1):S237-44
references.pmid: 12407599
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W469-73
references.pmid: 20513649
references.citation: Aliment Pharmacol Ther. 2014 Mar;39(5):478-87
references.pmid: 24387618
references.citation: Clin Liver Dis (Hoboken). 2014 Apr 01;3(3):65-68
references.pmid: 30992888
references.citation: J Med Chem. 2006 Nov 30;49(24):6950-3
references.pmid: 17125247
references.citation: Aliment Pharmacol Ther. 2014 Apr;39(7):686-98
references.pmid: 24612116
references.citation: Drugs. 2014 Feb;74(2):273-82
references.pmid: 24442794
references.citation: Drug Discov Today Technol. 2004 Dec;1(4):337-41
references.pmid: 24981612
references.citation: World J Gastroenterol. 2014 Mar 21;20(11):2941-7
references.pmid: 24659884
references.citation: Eur Rev Med Pharmacol Sci. 2012 May;16(5):667-71
references.pmid: 22774409
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Gene. 1992 Aug 15;117(2):229-32
references.pmid: 1322345
references.citation: Curr Med Chem. 2013;20(30):3733-42
references.pmid: 23848533
references.citation: Virology. 1992 Oct;190(2):894-9
references.pmid: 1325713
references.citation: Bioinformation. 2013 Aug 07;9(14):710-4
references.pmid: 23976825
references.citation: Drug Discov Ther. 2007 Aug;1(1):14-22
references.pmid: 22504360
references.citation: Curr Neuropharmacol. 2008 Sep;6(3):179-92
references.pmid: 19506719
references.citation: Curr Opin Chem Biol. 2004 Jun;8(3):339-45
references.pmid: 15183334
references.citation: Nat Struct Biol. 1999 Oct;6(10):937-43
references.pmid: 10504728
references.citation: Hepatology. 2014 Jan;59(1):318-27
references.pmid: 24115039
references.citation: Drug Metab Dispos. 2009 Mar;37(3):658-64
references.pmid: 19056915
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Life Sci. 2005 Dec 22;78(5):431-41
references.pmid: 16198377
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W623-33
references.pmid: 19498078
references.citation: J Biol Chem. 2006 Apr 14;281(15):9833-6
references.pmid: 16407182
references.citation: Front Pharmacol. 2014 Jul 28;5:174
references.pmid: 25120485
references.citation: J Med Chem. 2003 Aug 14;46(17):3572-80
references.pmid: 12904062
references.citation: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references.pmid: 15667143
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D668-72
references.pmid: 16381955
references.citation: Nat Rev Microbiol. 2007 Jun;5(6):453-63
references.pmid: 17487147
references.citation: Bioinformatics. 2013 Oct 15;29(20):2588-95
references.pmid: 23975762
references.citation: Antiviral Res. 1989 Sep;12(2):55-74
references.pmid: 2688551
references.citation: J Biol Chem. 2005 Aug 19;280(33):29765-70
references.pmid: 15955819
references.citation: Drug Discov Today. 2008 Oct;13(19-20):894-901
references.pmid: 18691670
references.citation: Curr Med Chem. 2010;17(32):3806-26
references.pmid: 20858218
references.citation: Viruses. 2012 Oct 17;4(10):2197-217
references.pmid: 23202460
references.citation: Protein Eng. 1995 Feb;8(2):127-34
references.pmid: 7630882
references.citation: Eur J Med Chem. 2004 Mar;39(3):235-40
references.pmid: 15051171
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13034-9
references.pmid: 10557268
references.citation: Mol Pharm. 2013 Apr 1;10(4):1191-206
references.pmid: 23253040
references.citation: J Ethnopharmacol. 2012 Dec 18;144(3):545-54
references.pmid: 23026306
references.citation: Cell Mol Life Sci. 2001 May;58(5-6):737-47
references.pmid: 11437235
references.citation: ChemMedChem. 2009 Oct;4(10):1695-713
references.pmid: 19672916
references.citation: Am Fam Physician. 1998 Jan 1;57(1):107-16
references.pmid: 9447218
references.citation: World J Gastroenterol. 2007 May 7;13(17):2406-15
references.pmid: 17552023
references.citation: J Med Chem. 2000 Oct 19;43(21):3867-77
references.pmid: 11052792
references.citation: Am Fam Physician. 2007 Aug 1;76(3):391-6
references.pmid: 17708140
references.citation: Drug Des Devel Ther. 2014 Dec 18;9:187-98
references.pmid: 25565772