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Int. J. Mol. Sci. 2011, 12(2), 1089-1100; doi:10.3390/ijms12021089

Design of New Competitive Dengue Ns2b/Ns3 Protease Inhibitors—A Computational Approach

Department of Chemistry, Faculty of Science, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia
Author to whom correspondence should be addressed.
Received: 20 December 2010 / Revised: 25 January 2011 / Accepted: 8 February 2011 / Published: 9 February 2011
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)
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Dengue is a serious disease which has become a global health burden in the last decade. Currently, there are no approved vaccines or antiviral therapies to combat the disease. The increasing spread and severity of the dengue virus infection emphasizes the importance of drug discovery strategies that could efficiently and cost-effectively identify antiviral drug leads for development into potent drugs. To this effect, several computational approaches were applied in this work. Initially molecular docking studies of reference ligands to the DEN2 NS2B/NS3 serine protease were carried out. These reference ligands consist of reported competitive inhibitors extracted from Boesenbergia rotunda (i.e., 4-hydroxypanduratin A and panduratin A) and three other synthesized panduratin A derivative compounds (i.e., 246DA, 2446DA and 20H46DA). The design of new lead inhibitors was carried out in two stages. In the first stage, the enzyme complexed to the reference ligands was minimized and their complexation energies (i.e., sum of interaction energy and binding energy) were computed. New compounds as potential dengue inhibitors were then designed by putting various substituents successively on the benzyl ring A of the reference molecule. These substituted benzyl compounds were then computed for their enzyme-ligand complexation energies. New enzyme-ligand complexes, exhibiting the lowest complexation energies and closest to the computed energy for the reference compounds, were then chosen for the next stage manipulation and design, which involved substituting positions 4 and 5 of the benzyl ring A (positions 3 and 4 for 2446DA) with various substituents.
Keywords: dengue NS2B/NS3 protease; molecular docking; interaction energy; binding energy; complexation energy dengue NS2B/NS3 protease; molecular docking; interaction energy; binding energy; complexation energy
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Frimayanti, N.; Chee, C.F.; Zain, S.M.; Rahman, N.A. Design of New Competitive Dengue Ns2b/Ns3 Protease Inhibitors—A Computational Approach. Int. J. Mol. Sci. 2011, 12, 1089-1100.

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