Cyclopropane‐Based Peptidomimetics Mimicking Wide‐Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization. Issue 13 (1st February 2017)

• Record Type: Journal Article
• Authors: Mizuno, Akira; Kameda, Tomoshi; Kuwahara, Tomoki; Endoh, Hideyuki; Ito, Yoshihiko; Yamada, Shizuo; Hasegawa, Kimiko; Yamano, Akihito; Watanabe, Mizuki; Arisawa, Mitsuhiro; Shuto, Satoshi
• Is Part Of: Chemistry. Volume 23:Issue 13(2017)
• Page Start: 3159
• Page End: 3168
• Publication Date: 2017-02-01
• Subjects: chemical space -- conformation analysis -- drug design -- peptidomimetics -- three-dimensional structural diversity; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201605312
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : Orientation is key : Detailed conformational analyses revealed that cyclopropane provides conformationally restricted peptidomimetics with high three‐ dimensional (3D) structural diversity, mimicking broad peptide secondary structures. The presented strategy is effective not only for designing non‐peptidic ligands but also for rational optimization of these ligands based on the plausible target‐binding conformation without requiring 3D structural information of the target and its peptide ligands.