title: Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization.
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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mizuno
authors.affiliation: Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7, Aomi, Koutou-ku, Tokyo, 135-0064, Japan.
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Kameda
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kuwahara
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Endoh
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Yata, Suruga-ku, Shizuoka, Shizuoka, 422-8526, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Yata, Suruga-ku, Shizuoka, Shizuoka, 422-8526, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Rigaku Corporation, Application Laboratories, 3-9-12, Matsubara-cho, Akishima, Tokyo, 196-8666, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Rigaku Corporation, Application Laboratories, 3-9-12, Matsubara-cho, Akishima, Tokyo, 196-8666, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamano
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.|Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
authors.forename: Satoshi
authors.identifier: http://orcid.org/0000-0001-7850-8064
authors.initials: S
authors.lastname: Shuto
mesh_terms: D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D044101:Receptors, Melanocortin / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; D008024:Ligands; D010455:Peptides; D057786:Peptidomimetics; D044101:Receptors, Melanocortin
keywords: chemical space; conformation analysis; drug design; peptidomimetics; three-dimensional structural diversity