Computer-aided rational molecular design of argifin-derivatives with increased inhibitory activity against chitinase B from Serratia marcescens.

Abstract

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).

• Authors: Hiroaki Gouda, Toshiaki Sunazuka, Kanami Iguchi, Akihiro Sugawara, Tomoyasu Hirose, Yoshihiko Noguchi, Yoshifumi Saito, Yuichi Yanai, Tsuyoshi Yamamoto, Takeshi Watanabe, Kazuro Shiomi, Satoshi Omura, Shuichi Hirono
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 19 Issue 10 Pg. 2630-3 (May 15 2009) ISSN: 1464-3405 [Electronic] England
• PMID: 19395258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Peptides, Cyclic
• Pesticides
• argifin
• Chitinases

Topics

• Amino Acid Sequence
• Chitinases (antagonists & inhibitors, metabolism)
• Computer-Aided Design
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Gliocladium (chemistry)
• Kinetics
• Peptides, Cyclic (chemistry, isolation & purification, pharmacology)
• Pesticides (chemical synthesis, chemistry, pharmacology)
• Serratia marcescens (enzymology)
• Structure-Activity Relationship
• Thermodynamics