Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 19, Issue 10, Pages 2630-2633Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.04.013
Keywords
In silico drug design; Molecular dynamics; Docking; Binding free energy
Categories
Funding
- Japan Society for the Promotion of Science [KAKENHI 19590043, KAKENHI 18590015]
- Takeda Science Foundation
- Mochida Memorial Foundation
- Kitasato University Research
- Grants-in-Aid for Scientific Research [21590122, 21590046] Funding Source: KAKEN
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Argifin, a novel pentapeptide chitinase inhibitor isolated from Gliocladium fungal culture, is a promising candidate for the development of new fungicides, insecticides, and anti-asthma medications. In this study, we undertook rational molecular design of argifin-derivatives and tested them against chitinase B from Serratia marcescens (SmChiB). The work involved molecular dynamics simulation with explicit water molecules, the molecular docking calculation, and free-energy analysis using the molecular mechanics Poisson-Boltzmann surface area method. The custom-designed derivatives were synthesized via effective solid phase synthesis, developed recently in our laboratory, and their inhibitory activities were measured against SmChiB. Finally, we identified and obtained a derivative which exhibited 28-fold more inhibition than argifin itself, a compound in which the D-Ala(5) of argifin was replaced with D-Leu and the 4-benzylpiperdine was attached to L-Asp(4). (C) 2009 Elsevier Ltd. All rights reserved.
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