Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 52, Issue -, Pages 103-113Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2014.06.008
Keywords
Dengue; DENV2; NS2B/NS3 protease; Allosteric inhibitors
Categories
Funding
- APEX funding (Malaysia Ministry of Higher Education)
- Universiti Sains Malaysia
- XESEDE [TG-MCB100110]
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The allosteric pocket of the Dengue virus (DENV2) NS2B/NS3 protease, which is proximal to its catalytic triad, represents a promising drug target (Othman et al., 2008). We have explored this binding site through large-scale virtual screening and molecular dynamics simulations followed by calculations of binding free energy. We propose two mechanisms for enzyme inhibition. A ligand may either destabilize electronic density or create steric effects relating to the catalytic triad residues NS3-H1S51, NS3-ASP75, and NS3-SER135. A ligand may also disrupt movement of the C-terminal of NS2B required for inter-conversion between the open and closed conformations. We found that chalcone and adenosine derivatives had the top potential for drug discovery hits, acting through both inhibitory mechanisms. Studying the molecular mechanisms of these compounds might be helpful in further investigations of the allosteric pocket and its potential for drug discovery. (C) 2014 Elsevier Inc. All rights reserved,
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