In silico development of a novel putative inhibitor of the 3C protease of Coxsackievirus B3 with a benzene sulfonamide skeleton

Ajay Kumar Timiri, Syed Hussain Basha, Rana Abdelnabi, Johan Neyts, Pieter Leyssen, Barij Nayan Sinha, Venkatesan Jayaprakash


Availability of X-ray crystal structure of 3C protease of several enteroviruses provided an opportunity for in silico drug design and development approach. Presented study is aimed at designing a novel compound targeting 3C protease of Coxsackievirus (CVB3), which is reported frequently to cause myocarditis in North America and Europe. A pthalimido-sulfonamide derivative (ZINC13799063) was identified through high-throughput virtual screening (HTVS) approach from the top HITs. A small library of phalimido-sulphonamides was enumerated to find a potential LEAD. Compound 17 from the library was found to inhibit CVB3 selectively in cell based antiviral assay at a concentration of EC50=1.0±0.1 µM with a selectivity index of >140. Molecular dynamics study was performed to investigate the selective inhibition of CVB3 over CVB4.


Coxsackie virus B3; Virtual Screening; protease inhibitors; Sulfonamide; Molecular dynamics

Full Text:



Bowles, N.; Olsen, E.; Richardson, P.; Archard, L. Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1986, 327 (8490), 1120-1123.

Dalldorf, G. The Coxsackie Viruses*. Am J Public Health Nations Health 1950, 40 (12), 1508-1511.

Dalldorf, G.; Sickles, G. M. An unidentified, filtrable agent isolated from the feces of children with paralysis. Science 1948, 108 (2794), 61-62.

Javett, S.; Heymann, S.; Mundel, B.; Pepler, W.; Lurie, H.; Gear, J.; Measroch, V.; Kirsch, Z. Myocarditis in the newborn infant: A study of an outbreak associated with Coxsackie group B virus infection in a maternity home in Johannesburg. J Pediatr 1956, 48 (1), 1-22.

Brightman, V.; Scott, T. M.; Westphal, M.; Boggs, T. An outbreak of coxsackie B-5 virus infection in a newborn nursery. J Pediatr 1966, 69 (2), 179-192.

Sainani, G. S.; Krompotic, E.; Slodki, S. J. Adult heart disease due to the Coxsackie virus B infection. Medicine 1968, 47 (2), 133-147.

Smith, W. Coxsackie B myopericarditis in adults. Am Heart J 1970, 80 (1), 34-46.

Knipe, D.; Howley, P. M.; Griffin, D.; Lamb, R.; Martin, M.; Roizman, B. Field's Virology. 2001, Vol 1, 5th Ed. Lippincott Williams & Wilkins, Philadelphia (EUA)

Abzug, M. J. Prognosis for neonates with enterovirus hepatitis and coagulopathy. Pediatr Infect Dis J 2001, 20 (8), 758-763.

Kawashima, H.; Ryou, S.; Nishimata, S.; Ioi, H.; Kashiwagi, Y.; Iizumi, M.; Takami, T.; Sasamoto, M.; Takekuma, K.; Hoshika, A. Enteroviral hepatitis in children. Pediatr Int 2004, 46 (2), 130-134.

van der Schaar, H. M.; Leyssen, P.; Thibaut, H. J.; De Palma, A.; van der Linden, L.; Lanke, K. H.; Lacroix, C.; Verbeken, E.; Conrath, K.; MacLeod, A. M. A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ. Antimicrob Agents Chemother 2013, 57 (10), 4971-4981.

Si, X.; McManus, B. M.; Zhang, J.; Yuan, J.; Cheung, C.; Esfandiarei, M.; Suarez, A.; Morgan, A.; Luo, H. Pyrrolidine dithiocarbamate reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway. J Virol 2005, 79 (13), 8014-8023.

Harki, D. A.; Graci, J. D.; Galarraga, J. E.; Chain, W. J.; Cameron, C. E.; Peterson, B. R. Synthesis and antiviral activity of 5-substituted cytidine analogues: identification of a potent inhibitor of viral RNA-dependent RNA polymerases. J Med Chem 2006, 49 (21), 6166-6169.

Abdel-Mageed, W. M.; Bayoumi, S. A.; Chen, C.; Vavricka, C. J.; Li, L.; Malik, A.; Dai, H.; Song, F.; Wang, L.; Zhang, J. Benzophenone C-glucosides and gallotannins from mango tree stem bark with broad-spectrum anti-viral activity. Bioorg Med Chem 2014, 22 (7), 2236-2243.

Lee, S. M.; Kim, S. M.; Lee, Y. H.; Kim, W. J.; Park, J. K.; Park, Y. I.; Jang, W. J.; Shin, H.-D.; Synytsya, A. Macromolecules isolated from Phellinus pini fruiting body: chemical characterization and antiviral activity. Macromol Res 2010, 18 (6), 602-609.

Liu, Q.; Wang, Y.-F.; Chen, R.-J.; Zhang, M.-Y.; Wang, Y.-F.; Yang, C.-R.; Zhang, Y.-J. Anti-coxsackie virus B3 norsesquiterpenoids from the roots of Phyllanthus emblica. J Nat Prod 2009, 72 (5), 969-972.

Deng, Y.-P.; Liu, Y.-Y.; Liu, Z.; Li, J.; Zhao, L.-M.; Xiao, H.; Ding, X.-H.; Yang, Z.-Q. Antiviral activity of Folium isatidis derived extracts in vitro and in vivo. Am J Chin Med 2013, 41 (04), 957-969.

Binford, S.; Maldonado, F.; Brothers, M.; Weady, P.; Zalman, L.; Meador, J.; Matthews, D.; Patick, A. Conservation of amino acids in human rhinovirus 3C protease correlates with broad-spectrum antiviral activity of rupintrivir, a novel human rhinovirus 3C protease inhibitor. Antimicrob Agents Chemother 2005, 49 (2), 619-626.

Gorbalenya, A.; Svitkin, Y. V.; Kazachkov, Y. A.; Agol, V. Encephalomyocarditis virus-specific polypeptide p22 is involved in the processing of the viral precursor polypeptides. FEBS Lett 1979, 108 (1), 1-5.

Padalko, E. New strategies for the treatment of coxsackievirus-induced myocarditis. 2005, p. 333, Leuven University Press, Leuven, Belgium

Kuo, R.-L.; Kung, S.-H.; Hsu, Y.-Y.; Liu, W.-T. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol 2002, 83 (6), 1367-1376.

Weng, K.-F.; Li, M.-L.; Hung, C.-T.; Shih, S.-R. Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation. PLoS Pathog 2009, 5 (9), e1000593-e1000593.

Li, M.-L.; Hsu, T.-A.; Chen, T.-C.; Chang, S.-C.; Lee, J.-C.; Chen, C.-C.; Stollar, V.; Shih, S.-R. The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology 2002, 293 (2), 386-395.

Tong, L. Viral proteases. Chem Rev 2002, 102 (12), 4609-4626.

Badrinarayan, P.; Narahari Sastry, G. Virtual high throughput screening in new lead identification. Comb Chem High Throughput Screen 2011, 14 (10), 840-860.

Timiri, A. K.; Selvarasu, S.; Kesherwani, M.; Vijayan, V.; Sinha, B. N.; Devadasan, V.; Jayaprakash, V. Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors. Bioorg Chem 2015, 62, 74-82.

Tang, G.; Lin, X.; Qiu, Z.; Li, W.; Zhu, L.; Wang, L.; Li, S.; Li, H.; Lin, W.; Yang, M. Design and synthesis of benzenesulfonamide derivatives as potent anti-influenza hemagglutinin inhibitors. ACS Med Chem Lett 2011, 2 (8), 603-607.

Bano, S.; Javed, K.; Ahmad, S.; Rathish, I.; Singh, S.; Alam, M. Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents. Eur J Med Chem 2011, 46 (12), 5763-5768.

Bashir, R.; Ovais, S.; Yaseen, S.; Hamid, H.; Alam, M.; Samim, M.; Singh, S.; Javed, K. Synthesis of some new 1, 3, 5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents. Bioorg Med Chem Lett 2011, 21 (14), 4301-4305.

Ghorab, M. M.; Ragab, F. A.; Hamed, M. M. Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety. Eur J Med Chem 2009, 44 (10), 4211-4217.

Brzozowski, Z. 2-Mercapto-N-(azolyl) benzenesulphonamides III. Synthesis of some new 2-mercapto-N-(5-amino-1, 2, 4-triazol-3-yl) benzenesulphonamide derivatives with potential anti-HIV or anticancer activity. Acta Pol Pharm 1995, 53 (4), 269-276.

Wang, H.-M.; Liang, P.-H. Picornaviral 3C protease inhibitors and the dual 3C protease/coronaviral 3C-like protease inhibitors. Expert Opin Ther Pat 2010, 20 (1), 59-71.

Kang, Y.; Chatterjee, N. K.; Nodwell, M. J.; Yoon, J. W. Complete nucleotide sequence of a strain of coxsackie B4 virus of human origin that induces diabetes in mice and its comparison with nondiabetogenic coxsackie B4 JBV strain. J Med Virol 1994, 44 (4), 353-361.

Costenaro, L.; Kaczmarska, Z.; Arnan, C.; Janowski, R.; Coutard, B.; Solà, M.; Gorbalenya, A. E.; Norder, H.; Canard, B.; Coll, M. Structural basis for antiviral inhibition of the main protease, 3C, from human enterovirus 93. J Virol 2011, 85 (20), 10764-10773.

Shivakumar, D.; Williams, J.; Wu, Y.; Damm, W.; Shelley, J.; Sherman, W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 2010, 6 (5), 1509-1519.

Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J Chem Phys 1983, 79 (2), 926-935.

Price, D. J.; Brooks, C. L. Detailed considerations for a balanced and broadly applicable force field: A study of substituted benzenes modeled with OPLS‐AA. J Comput Chem 2005, 26 (14), 1529-1541.

Shinoda, W.; Mikami, M. Rigid‐body dynamics in the isothermal‐isobaric ensemble: A test on the accuracy and computational efficiency. J Comput Chem 2003, 24 (8), 920-930.

Nosé, S. A unified formulation of the constant temperature molecular dynamics methods. J Chem Phys 1984, 81 (1), 511-519.




  • There are currently no refbacks.


                              VENSEL PUBLICATIONS@2019

 20, Keelavaithianathapuram, 4th Street, Madurai-625 018 (TN), India