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Cyclopropane‐Based Peptidomimetics Mimicking Wide‐Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization
Author(s) -
Mizuno Akira,
Kameda Tomoshi,
Kuwahara Tomoki,
Endoh Hideyuki,
Ito Yoshihiko,
Yamada Shizuo,
Hasegawa Kimiko,
Yamano Akihito,
Watanabe Mizuki,
Arisawa Mitsuhiro,
Shuto Satoshi
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605312
Subject(s) - peptidomimetic , cyclopropane , chemistry , peptide , ligand (biochemistry) , stereochemistry , rational design , combinatorial chemistry , receptor , biochemistry , materials science , nanotechnology , organic chemistry , ring (chemistry)
Detailed conformational analyses of our previously reported cyclopropane‐based peptidomimetics and conformational analysis‐driven ligand optimization are described. Computational calculations and X‐ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three‐dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main‐chain and side‐chain conformations. Based on these analyses, a lead stereoisomer targeting melanocortin receptors was identified, and its potency and subtype selectivity were improved by further derivatization. The presented strategy is effective not only for designing non‐peptidic ligands from a peptide ligand but also for the rational optimization of these ligands based on the plausible target‐binding conformation without requiring the three‐ dimensional structural information of the target and its peptide ligands.