Lead Optimization Studies Towards Finding NS2B/NS3 Protease Targetspecific Inhibitors as Potential Anti-dengue Drug-like Compounds

Author(s): Murugaboopathi Gurusamy*, Jainul Fathima Abdul

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Dengue Fever is a major threatening global health issue caused by a mosquito-borne pathogen. Even though some anti-viral drugs are now available to reduce the disease severity. Still, there is a need of better drug compound to combat with dengue fever. The NS2B/NS3 protease is a major therapeutic drug target for Insilco drug discovery.

Materials & Methods: Previously, we have performed a pharmacophore features based virtual screening studies, which has led to the identification of ZINC92615064 compound as a potent NS2B/NS3 protease inhibitor and demonstrated its potential to act as anti-dengue drug-like compound using computational approaches. In this present study, the identified lead compound ZINC92615064 has been made to undergo scaffold hopping based novel library generation, and the resulted novel library of compounds has been virtually screened on to NS2B/NS3 protease towards identifying novel proprietary scaffold of compound which is acting as a potent inhibitor for the given drug target of NS2B/NS3.

Result & Conclusion: A total of 16,847 novel designed compounds library was generated using the scaffold hopping technology based on the structure of the lead compound ZINC92615064. Out of which, compound design no. 3718 has shown the best binding potential with a predicted IC50 value of 417.13 nM along with a permissible range of ADMET properties based on its descriptor values. This NS2B/NS3 protease in complex with compound 3718 was subjected to a rigorous molecular dynamic simulation study to further validate this complex thermodynamic stability, along with the aim to reveal the underlying molecular level interactions and potential mode of action.

Keywords: NS2B/NS3 protease, dengue, scaffold hopping, virtual screening, ADMET, drug.

Low J, Ooi E, Vasudevan S. Current Status of Dengue Therapeutics Research and Development. J Infect Dis 2017; 215(suppl_2): S96-S102.
Dengue and severe dengue [Internet]. World Health Organization. 2018. Available from http://www.who.int/en/news-room/fact-sheets/detail/dengue-and-severe-dengue [cited 27 June 2018].
Chaudhuri N, Vithyavathi S, Sankar K. Clinical and laboratory profile of different dengue sub types in dengue virus infection. Int J Res Med Sci 2016; 4(3): 743-8.
Chen S, Wu Z, Wang M, Cheng A. Innate immune evasion mediated by flaviviridae non-structural proteins. Viruses 2017; 9(10): 291.
Normile D. Surprising new dengue virus throws a spanner in disease control efforts. Science 2013; 342(6157): 415-5.
Vannice KS, Durbin A, Hombach J. Status of vaccine research and development of vaccines for dengue. Vaccine 2016; 34(26): 2934-8.
Velmurugan D, Mythily U, Rao K. Design and docking studies of peptide inhibitors as potential antiviral drugs for dengue Virus Ns2b/Ns3 protease. Protein Pept Lett 2013; 21(8): 815-27.
Katsila T, Spyroulias GA, Patrinos GP, Matsoukas MT. Computational approaches to target identification and drug discovery. Comput Struct Biotechnol J 2016; 14: 177-84.
Fathima AJ, Murugaboopathi G, Selvam P. Computational approaches in drug discovery: An overview. Int J Adv Res Sci and Eng 2017; 6(7): 189-95.
Hung C, Chen C. Computational approaches for drug discovery. Drug Dev Res 2014; 75(6): 412-8.
Wu H, Bock S, Snitko M, et al. Novel dengue virus NS2B/NS3 protease inhibitors. Antimicrob Agents Chemother 2014; 59(2): 1100-9.
Mukhametov A, Newhouse E, Aziz N, Saito J, Alam M. Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition. J Mol Graph Model 2014; 52: 103-13.
Hariono Maywan, Ezatul E. Kamarulzaman, and Habibah A. Wahab. "Computational design of dengue type-2 NS2B/NS3 protease inhibitor: 2D/3D QSAR of quinoline and its molecular docking." 3rd International Conference on Computation for Science and Technology (ICCST-3). Atlantis Press. 2015.
Ashfaq U. Tahir ul QM, Kiran S, et al Discovery of novel dengue NS2B/NS3 protease inhibitors using pharmacophore modeling and molecular docking based virtual screening of the zinc database. Int J Pharmacol 2016; 12(6): 621-32.
Brecher M, Li Z, Liu B, et al. A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease. PLoS Pathog 2017; 13(5)e1006411
Fathima A, Murugaboopathi G, Selvam P. Pharmacophore Mapping of ligand based virtual screening, molecular docking and molecular dynamic simulation studies for finding potent NS2B/NS3 Protease Inhibitors as potential anti-dengue drug compounds. Curr Bioinform 2018. [E-pub Ahead of Print].
Maestro. New York: Schrödinger, LLC 2013.
VLifeMDS: Molecular Design Suite, VLife Sciences Technologies Pvt. Ltd., Pune, India 2010.
Latha M, Saddala M. Molecular docking based screening of a simulated HIF-1 protein model for potential inhibitors. Bioinformation 2017; 13(11): 388-93.
Goodsell D, Morris G, Olson A. Automated docking of flexible ligands: Applications of autodock. J Mol Recognit 1996; 9(1): 1-5.
Molecular Properties Prediction - Osiris Property Explorer [Internet]. Organic-chemistry.org. 2018 [cited 12 February 2018]. Available from.http://www.organic-chemistry.org/prog/peo/
Sussman J, Lin D, Jiang J, et al. Protein Data Bank (PDB): Database of three-dimensional structural information of biological macromolecules. Acta Crystallogr D Biol Crystallogr 1998; 54(6): 1078-84.
Reddy S, Reddy K, Kumari V, Basha S. Molecular docking and dynamic simulation studies evidenced plausible immunotherapeutic anticancer property by Withaferin A targeting indoleamine 2,3-dioxygenase. J Biomol Struct Dyn 2015; 33(12): 2695-709.
Morris G, Goodsell D, Halliday R, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19(14): 1639-62.
Maestro-Desmond Interoperability Tools, version 3.6, Schrödinger, New York, NY 2013.
Jorgensen W, Maxwell D, Tirado-Rives J. Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids. J Am Chem Soc 1996; 118(45): 11225-36.
Mark P, Nilsson L. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. J Phys Chem A 2001; 105(5): 9954-60.
Lipinski C. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol 2004; 1(43): 337-41.
Lobanov M, Bogatyreva N, Galzitskaya O. Radius of gyration as an indicator of protein structure compactness. Mol Biol 2008; 42(4): 623-8.
DuBay K, Geissler P. Calculation of proteins’ total side-chain torsional entropy and its influence on protein-ligand interactions. J Mol Biol 2009; 391(2): 484-97.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 14 October, 2019
Page: [307 - 314]
Pages: 8
DOI: 10.2174/1570163815666180709155131
Price: $65

Article Metrics

PDF: 34