Research Article

Rational Discovery of Dengue Type 2 Non-competitive Inhibitors

  1. Choon Han Heh1,5,
  2. Rozana Othman1,5,*,
  3. Michael J. C. Buckle1,5,
  4. Yusrizam Sharifuddin2,5,
  5. Rohana Yusof3,5,
  6. Noorsaadah Abd. Rahman4,5

DOI: 10.1111/cbdd.12122

Additional Information

Author Information

  1. 1

    Department of Pharmacy, Faculty of Medicine, University of Malaya

  2. 2

    Biohealth Science Programme, Institute of Biological Sciences, University of Malaya

  3. 3

    Department of Molecular Medicine, Faculty of Medicine, Univeristy of Malaya

  4. 4

    Department of Chemistry, Faculty of Science, Univeristy of Malaya, Kuala Lumpur, Malaysia

  5. 5

    Drug Design and Development Research Group, University of Malaya

* Corresponding Author:
Name: Dr. Rozana Othman
Postal Address: Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Telephone: +603-7967 5796
Fax: +603-7967 4964
Email Address: rozanaothman@um.edu.my

  1. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1111/cbdd.12122

Publication History

  1. Accepted manuscript online: 19 FEB 2013 11:25PM EST
  2. Manuscript Accepted: 12 FEB 2013
  3. Manuscript Revised: 16 JAN 2013
  4. Manuscript Received: 20 NOV 2012

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Keywords:

  • Rational Drug Discovery;
  • Dengue virus type 2;
  • DEN-2;
  • NS2B/NS3;
  • AutoDock Virtual Screening;
  • Small Compounds;
  • Protease Assay

Abstract

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13,341 small compounds, with the backbone structures of chalcone, flavanone and flavone, available from the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared to the standard ligand. Inhibition assay of the selected top ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared to the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents.

© 2013 John Wiley & Sons A/S

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