title: Rational discovery of dengue type 2 non-competitive inhibitors.
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 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 NS2B/NS3 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.
authors: Drug Design and Development Research Group, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors: Choon H
authors: CH
authors: Heh
authors: Rozana
authors: R
authors: Othman
authors: Michael J C
authors: MJ
authors: Buckle
authors: Yusrizam
authors: Y
authors: Sharifuddin
authors: Rohana
authors: R
authors: Yusof
authors: Noorsaadah A
authors: NA
authors: Rahman
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000201:enzymology*; D047309:Flavones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013777:Tetrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013816:Thermodynamics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D047309:Flavones; D011480:Protease Inhibitors; D020365:RNA Helicases; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D013777:Tetrazoles; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases