Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 23, Issue 13, Pages 3159-3168Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201605312
Keywords
chemical space; conformation analysis; drug design; peptidomimetics; three-dimensional structural diversity
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Funding
- Japan Society for the Promotion of Science [15H02495, 24390023, 2310550201, 2179000300]
- Grants-in-Aid for Scientific Research [17K15476, 16H05106, 24390023, 15H02495, 16H01026, 15KT0063] Funding Source: KAKEN
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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.
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