Portal de Periódicos da CAPES

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

2009; Elsevier BV; Volume: 19; Issue: 10 Linguagem: Inglês

10.1016/j.bmcl.2009.04.013

1464-3405

Hiroaki Gouda, Toshiaki Sunazuka, Kanami Iguchi, Akihiro Sugawara, Tomoyasu Hirose, Yoshihiko Noguchi, Yoshifumi Saito, Yuichi Yanai, Tsuyoshi Yamamoto, Takeshi Watanabe, Kazuro Shiomi, Satoshi Ōmura, Shuichi Hirono,

Carbohydrate Chemistry and Synthesis

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).