QSAR Studies on Thiazole Derivatives as HCV NS5A Inhibitors via CoMFA and CoMSIA Methods

Author(s): Jiayu Li, Wenyue Tian, Diaohui Gao, Yuying Li, Yiqun Chang, Jun Xu, Junxia Zheng*, Pinghua Sun*.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 4 , 2019

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Abstract:

Background: Hepatitis C Virus (HCV) infection is the major cause of hepatitis after transfusion. And HCV Nonstructural Protein 5A (NS5A) inhibitors have become a new hotspot in the study of HCV inhibitors due to their strong antiviral activity, rapid speed of viral removing and broad antiviral spectrum.

Methods: Forty-five NS5A inhibitors were chosen to process three-dimensional quantitative structure- activity relationship (3D-QSAR) by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. A training set consisting of 30 compounds was applied to establish the models and a test set consisting of 15 compounds was applied to do the external validation.

Results: The CoMFA model predicted a q2 value of 0.607 and an r2 value of 0.934. And the CoMSIA model predicted a q2 value of 0.516 and an r2 value of 0.960 established on the effects of steric, electrostatic, hydrophobic and hydrogen-bond acceptor. 0.713 and 0.939 were the predictive correlation co-efficients (r2pred) of CoMFA and CoMSIA models, respectively.

Conclusion: These conclusions provide a theoretical basis for drug design and screening of HCV NS5A complex inhibitors.

Keywords: 3D-QSAR, thiazole derivatives, HCV, NS5A inhibitors, broad antiviral spectrum, strong antiviral activity.

[1]
Gong, Q.L.; Wang, J.; Fu-Chu, H.E. Advance in the research of the nonstructural protein NS2 of hepatitis C virus. Chinese Bullet. Life Sci., 2009, 01, 43-48.
[2]
Xiong, Y.L.; Zhang, C.J.; Wang, X.H.; Hepatitis, C. Virus genomic structure and function. Chin. J. Biochem. Mol. Biol., 2008, 07, 587-592.
[3]
Gao, M.; Nettles, R.E.; Belema, M.; Snyder, L.B.; Nguyen, V.N.; Fridell, R.A.; Serranowu, M.H.; Langley, D.R.; Sun, J.H.; Nd, O.B.D. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature, 2010, 465(7294), 96-100.
[4]
Ghany, M.G.; Strader, D.B.; Thomas, D.L.; Seeff, L.B. Diagnosis, management, and treatment of hepatitis C: An update. Hepatology, 2009, 49(4), 1335-1374.
[5]
Verma, J.; Khedkar, V.M.; Coutinho, E.C. 3D-QSAR in drug design-a review. Curr. Top. Med. Chem., 2010, 10(1), 95-115.
[6]
Yang, S.Y. Pharmacophore modeling and applications in drug discovery: Challenges and recent advances. Drug Discov. Today, 2010, 15(11), 444-450.
[7]
Kang, I.J.; Hsu, S.J.; Yang, H.Y.; Yeh, T.K.; Lee, C.C.; Lee, Y.C.; Tian, Y.W.; Song, J.S.; Hsu, T.A.; Chao, Y.S. A potent, selective, and orally bioavailable HCV NS5A inhibitor for treatment of Hepatitis C virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carbo-xamide. J. Med. Chem., 2016, 60(1), 228-247.
[8]
Lemmen, C.; Lengauer, T.; Klebe, G. FLEXS: A method for fast flexible ligand superposition. J. Med. Chem., 1998, 41(23), 4502-4520.
[9]
Polanski, J.; Walczak, B. The comparative molecular surface analysis (COMSA): A novel tool for molecular design. Comput. Chem., 2000, 24(5), 615-625.
[10]
Sit, S.Y.; Parker, R.A.; Motoc, I.; Han, W.; Balasubramanian, N.; Catt, J.D.; Brown, P.J.; Harte, W.E.; Thompson, M.D.; Wright, J.J. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J. Med. Chem., 1990, 33(11), 2982-2999.
[11]
Paterson, M.; Laxton, C.D.; Thomas, H.C.; Ackrill, A.M.; Foster, G.R. Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical response. Gastroenterology, 1999, 117(5), 1187-1197.
[12]
Lemmen, C.; Lengauer, T. Time-efficient flexible superposition of medium-sized molecules. J. Comput. Aided Mol. Des., 1997, 11(4), 357-368.
[13]
Bringmann, G.; Rummey, C. 3D QSAR investigations on antimalarial naphthylisoquinoline alkaloids by comparative molecular similarity indices analysis (CoMSIA), based on different alignment approaches. J. Chem. Inf. Comput. Sci., 2003, 43(1), 304-316.
[14]
Lemmen, C.; Lengauer, T. Computational methods for the structural alignment of molecules. J. Comput. Aided Mol. Des., 2000, 14(3), 215-232.
[15]
Silverman, B.D.; Platt, D.E. Comparative molecular moment analysis (CoMMA): 3D-QSAR without molecular superposition. J. Med. Chem., 1996, 39(11), 2129-2140.
[16]
Waller, C.L.; Oprea, T.I.; Chae, K.; Park, H.K.; Korach, K.S.; Laws, S.C.; Wiese, T.E.; Kelce, W.R.; Gray, L.E., Jr Ligand-based identification of environmental estrogens. Chem. Res. Toxicol., 1996, 9(8), 1240-1248.
[17]
Cavalli, A.; Poluzzi, E.; De Ponti, F.; Recanatini, M. Toward a pharmacophore for drugs inducing the long QT syndrome: Insights from a CoMFA study of HERG K+ channel blockers. J. Med. Chem., 2002, 45(18), 3844-3853.
[18]
Jiang, X.B.; Yan-Ping, L.I.; Zhuo-Rong, L.I. Research progress of HCV NS5A complex inhibitors. Acta. Pharmaceutica. Sinica., 2016, 09, 1378-1387.
[19]
Cao, H.; Cao, R.; Zhang, H.; Zheng, X.; Gao, D. Non-nucleoside inhibitors of NS5B polymerase binding to allosteric sites: 3D-QSAR and molecular docking studies. Curr. Med. Chem., 2008, 15(15), 1462-1477.
[20]
Chen, K.X.; Xie, H.Y.; Li, Z.G. QSAR analysis of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxi- de derivatives as novel inhibitors of hepatitis C virus NS5B polymerase. Acta Chim. Slov., 2009, 56(3), 684-693.
[21]
Yu, H.; Fang, Y.; Lu, X.; Liu, Y.; Zhang, H. Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors. Chem. Biol. Drug Des., 2014, 83(1), 89-105.
[22]
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20(4), 269-276.
[23]
Kumada, H.; Suzuki, Y.; Ikeda, K. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology, 2014, 59(6), 2083-2091.


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Article Details

VOLUME: 16
ISSUE: 4
Year: 2019
Page: [453 - 460]
Pages: 8
DOI: 10.2174/1570180815666180702153529
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