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Rational Discovery of Dengue Type 2 Non‐Competitive Inhibitors
Author(s) -
Heh Choon H.,
Othman Rozana,
Buckle Michael J. C.,
Sharifuddin Yusrizam,
Yusof Rohana,
Rahman Noorsaadah A.
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12122
Subject(s) - in silico , protease , chemistry , dengue fever , docking (animal) , stereochemistry , chalcone , rational design , flavanone , computational biology , non competitive inhibition , homology modeling , virtual screening , pharmacophore , biochemistry , enzyme , biology , virology , flavonoid , medicine , nursing , antioxidant , gene , genetics
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 NS 2 B / NS 3 protease. A homology model of the DEN ‐2 NS 2 B / NS 3 protease (using W est N ile V irus NS 2 B / NS 3 protease complex, 2 FP 7, 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 in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top‐ranking compounds against DEN ‐2 NS 2 B / NS 3 proteolytic activity resulted in significantly better inhibition compared with 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.