Novel indole derivatives as hepatitis C virus NS5B polymerase inhibitors: Pharmacophore modeling and 3D QSAR studies

  • G. Varun Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, AP.
  • M. Lokesh Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, AP.
  • M. Sandeep Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, AP.
  • Sajad Shahbazi Department of Biotechnology, Punjab University, Chandigarh.
  • Deepak Reddy Gade Dept. of Pharmaceutical Chemistry, JNTUA-OTRI, Anantapur, AP, India.
Keywords: Hepatites C Virus, NS5B, Indole, Pharmacophore Modeling, 3D QSAR, PHASE


Hepatitis C Virus (HCV) encodes its own RNA dependent RNA polymerase (NS5b) in order to replicate its genome. An efficient pharmacophore was identified, by executing structural analysis of a set of 49 indole-based inhibitors of the HCV NS5B polymerase. Identified pharmacophoric features, two hydrophobic regions, and 4 aromatic rings i.e. HHRRRR.649. Ligand based 3D-QSAR was performed, partial least square regression analysis was employed which gave a regression coefficient R2 of 0.98 and Q2 of 0.88, and Pearson-R of 0.96.


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Basu A, Jasu K, Jayaprakash V, Mishra N, Ojha P, Bhattacharya S. Development of CoMFA and CoMSIA models of cytotoxicity data of anti-HIV-1-phenylamino-1H-imidazole derivatives. Eur J Med Chem. 2009; 44: 2400-07.

Behrens SE, Tomei L, De Francesco R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. Eur Mol Biol Organ J. 1996; 15: 12-22.

Biswal BK, Cherney MM, Wang M, Chan L, Yannopoulos CG, Bilimoria D, Nicolas O, Bedard J, James MNG. Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by nonnucleoside inhibitors. J Biol Chem. 2005; 280: 18202-10.

Bressaneli S, Tomei L, Roussel A, Incitti I, Vitale RL, Mathieu M, De Francesco R, Rey FA. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. Proc Natl Acad Sci USA. 1999; 96: 13034-39.

Clin CJ. The global surden of Hepatitis C working group. Global Burden of Disease (GBD) for hepatitis C. Pharmacology 2009; 44: 20-29.

Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA. PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des. 2006; 20: 647-71.

El-serag HB. Hepatocellular carcinoma: Recent trends in United States. Gastroenterology 2004; 5: S27-34.

Golbraikh A, Tropsha A. Beware of q2!. J Mol Graphics Modell. 2002; 20: 269-76.

Banchavibulbhan KX, Yang W, Sannigrahi M, Velazquez F, Chan TY, Venkatraman S, Gopinandhan N, Kumar A, Zeng Q, Bennet F, Jiang Y, Lesburg CA, Duca J, Pinto P, Gavalas S, Huang Y, Wu W, Selyutin O, Agrawal S, Feld B, Huang HC, Li C, Cheng KC, Shih NY, Kozlowski JA, Resenclum SB, F. George Njoroge FG. Structure–activity relationship (SAR ) development and discovery of potent indole based inhibitors of the hepatitis c virus (HCV) NS5B polymerase. J Med Chem. 2012; 55: 754-65.

Lesburg CA, Cable MB, Ferrari E, Hong Z, Mannarino AF, Weber PC. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Biol. 1999; 6: 937-43.

Ligprep, version 2.6 Schrödinger, LLC, New York, 2013.

Love RA, Parge HE, Yu X, Hickey MJ, Diehl W, Gao J, Wriggers H, Ekker A, Wang L, Thomson JA, Dragovich PS, Fuhrman SA. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme. J Virol. 2003; 77: 7575-81.

Lu P, Wei X, Zhang R. CoMFA and CoMSIA 3D-QSAR studies on quionolone carboxylic acid derivatives inhibitors of HIV-1 integrase. Eur J Med Chem. 2010; 45: 3413-19.

PHASE, version 3.5, Schrödinger, LLC, New York, NY, 2013.

Rajendra Prasad VVS, Deepak Reddy G, Appaji D, Peters GJ, Mayur YC. Chemosensitizing acridones: In vitro calmodulin dependent cAMP phosphodiesterase inhibition, docking, pharmacophore modeling and 3D QSAR studies. J Mol Graphics Modell. 2013; 40: 116-24.

Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchiyama M. Epik: A software program for pKa prediction and protonation state generation for druglike molecules. J Comput Aided Mol Des. 2007; 21: 681-91.

Verna EC, Brown RS. Hepatitis C and liver transplantation: Enhancing outcomes and should patients be retransplanted. Clin Liver Dis. 2008; 12: 637-59.

Wang M, Ng KKS, Cherney MM, Chan L, Yannopoulos CG, Bedard J, Morin N, Nguyen-Ba N, Alaoui-Ismaili MH, Bethell RC, James MNG. Nonnucleoside analogue inhibitors bind to an allosteric site on HCV NS5b polymerase. J Biol Chem. 2003; 278: 9489-95.

How to Cite
Varun, G., M. Lokesh, M. Sandeep, S. Shahbazi, and D. R. Gade. “Novel Indole Derivatives As Hepatitis C Virus NS5B Polymerase Inhibitors: Pharmacophore Modeling and 3D QSAR Studies”. Bangladesh Journal of Pharmacology, Vol. 9, no. 3, July 2014, pp. 290-7, doi:10.3329/bjp.v9i3.18894.
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