High throughput virtual screening based discovery of dengue protease inhibitor

Sounak Bagchi, Uzma Alia, Faiz Mohammad, Mohd Usman Mohd Siddique


High throughput virtual screening (HTVS) has been proved a successful tool for getting LEADs in drug design and discovery. In an attempt to design new Dengue protease inhibitors, we performed HTVS using Zinc13 database containing 13,195,609 drug-like molecules. ZINC42678127 was identified as potential HIT against Dengue protease. It’s shape and electrostatic complimentary was found to be 0.608 and 0.078, respectively. Qikprop analysis of the compound complied with the Rule of Five (Ro5) and other drug- likeliness properties. Binding mode analysis of docked conformer of ZINC42678127, displayed favorable interaction with the active site residues of DENV protease. The identified HIT has a potential to become a LEAD against Dengue protease.


Dengue, Serine protease, NS2B/NS3, HTVS, Binding mode analysis

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Gubler, D. J. In Dengue/dengue haemorrhagic fever: history and current status, Novartis foundation symposium, Chichester; New York; John Wiley; 1999: 2006; p 3.

WHO report on global surveillance of epidemic-prone infectious diseases. 2000.

Austin, S. K.; Dowd, K. A.; Shrestha, B.; Nelson, C. A.; Edeling, M. A.; Johnson, S.; Pierson, T. C.; Diamond, M. S.; Fremont, D. H., Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope. PLoS Pathog 2012, 8 (10), e1002930.


Lok, S.-M.; Kostyuchenko, V.; Nybakken, G. E.; Holdaway, H. A.; Battisti, A. J.; Sukupolvi-Petty, S.; Sedlak, D.; Fremont, D. H.; Chipman, P. R.; Roehrig, J. T., Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Nat Struct Mol Biol 2008, 15 (3), 312-317.


Alcaraz-Estrada, S. L.; del Angel, R.; Padmanabhan, R., Construction of self-replicating subgenomic dengue virus 4 (DENV4) replicon. Dengue: Methods and Protocols 2014, 131-150.

Bhatt, S.; Gething, P. W.; Brady, O. J.; Messina, J. P.; Farlow, A. W.; Moyes, C. L.; Drake, J. M.; Brownstein, J. S.; Hoen, A. G.; Sankoh, O., The global distribution and burden of dengue. Nature 2013, 496 (7446), 504.


Murray, N. E. A.; Quam, M. B.; Wilder-Smith, A., Epidemiology of dengue: past, present and future prospects. Clin Epidemiol 2013, 5, 299. https://doi.org/10.2147/CLEP.S34440

Fields, B.; Knipe, D.; Howley, P.; Griffin, D., Fields virology, Lippincott Williams & Wilkins. Philadelphia, Pa 2001.

Yang, C.-C.; Hsieh, Y.-C.; Lee, S.-J.; Wu, S.-H.; Liao, C.-L.; Tsao, C.-H.; Chao, Y.-S.; Chern, J.-H.; Wu, C.-P.; Yueh, A., Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay. Antimicrob Agents Chemother 2011, 55 (1), 229-238.


Nitsche, C.; Behnam, M. A.; Steuer, C.; Klein, C. D., Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease. Antiviral Res 2012, 94 (1), 72-79.


Rodenhuis-Zybert, I. A.; Wilschut, J.; Smit, J. M., Dengue virus life cycle: viral and host factors modulating infectivity. Cell Mol Life Sci 2010, 67 (16), 2773-2786.


Hanley, K. A.; Weaver, S. C., Frontiers in Dengue Virus Research. Horizon Scientific Press: 2010.

Tomlinson, S. M.; Watowich, S. J., Anthracene-based inhibitors of dengue virus NS2B–NS3 protease. Antiviral Res 2011, 89 (2), 127-135.


Gao, Y.; Cui, T.; Lam, Y., Synthesis and disulfide bond connectivity–activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B–NS3 protease. Bioorg Med Chem 2010, 18 (3), 1331-1336.


Steuer, C.; Gege, C.; Fischl, W.; Heinonen, K. H.; Bartenschlager, R.; Klein, C. D., Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture. Bioorg Med Chem 2011, 19 (13), 4067-4074.


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.


Irwin, J. J.; Shoichet, B. K., ZINC− a free database of commercially available compounds for virtual screening. J Chem Inf Model 2005, 45 (1), 177-182.


OEChem, T., OpenEye Scientific Software. Inc., Santa Fe, NM, USA 2012.

Maestro, S., Version 9.2. LLC, New York 2011.

Schrodinger, L., Schrodinger Software Suite. New York: Schrödinger, LLC 2011.

Sastry, G. M.; Dixon, S. L.; Sherman, W., Rapid shape-based ligand alignment and virtual screening method based on atom/feature-pair similarities and volume overlap scoring. J Chem Inf Model 2011, 51 (10), 2455-2466.


Radhakrishnan, M. L.; Tidor, B., Specificity in molecular design: a physical framework for probing the determinants of binding specificity and promiscuity in a biological environment. J Phys Chem B 2007, 111 (47), 13419-13435.


Halgren, T., New Method for Fast and Accurate Binding‐site Identification and Analysis. Chem Biol Drug Des 2007, 69 (2), 146-148


DOI: http://dx.doi.org/10.14805/jphchem.2017.art92


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