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Computer-aided rational molecular design of argifin-derivatives with increased inhibitory activity against chitinase B from Serratia marcescens.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2009 May 15; Vol. 19 (10), pp. 2630-3. Date of Electronic Publication: 2009 Apr 09. - Publication Year :
- 2009
-
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).
- Subjects :
- Amino Acid Sequence
Chitinases metabolism
Computer-Aided Design
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacology
Gliocladium chemistry
Kinetics
Peptides, Cyclic isolation & purification
Peptides, Cyclic pharmacology
Pesticides chemical synthesis
Pesticides pharmacology
Structure-Activity Relationship
Thermodynamics
Chitinases antagonists & inhibitors
Enzyme Inhibitors chemistry
Peptides, Cyclic chemistry
Pesticides chemistry
Serratia marcescens enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 19
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 19395258
- Full Text :
- https://doi.org/10.1016/j.bmcl.2009.04.013