title: 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.affiliation: Kitasato University, Shirokane, Minato-ku, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.forename: Kanami
authors.initials: K
authors.lastname: Iguchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Saito
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yanai
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kazuro
authors.initials: K
authors.lastname: Shiomi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D000595:Amino Acid Sequence; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020462:Gliocladium / Q000737:chemistry; D007700:Kinetics; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D010575:Pesticides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012706:Serratia marcescens / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D010575:Pesticides; C413566:argifin; D002688:Chitinases