title: Biological diversity from a structurally diverse library: systematically scanning conformational space using a pyranose scaffold.
abstract: Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH(1)) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
authors.affiliation: Alchemia Ltd, Eight Mile Plains, Queensland 4113, Australia.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbenante
authors.forename: Bernd
authors.initials: B
authors.lastname: Becker
authors.forename: Sébastien
authors.initials: S
authors.lastname: Blanc
authors.forename: Chris
authors.initials: C
authors.lastname: Clark
authors.forename: Glenn
authors.initials: G
authors.lastname: Condie
authors.forename: Graeme
authors.initials: G
authors.lastname: Fraser
authors.forename: Matthias
authors.initials: M
authors.lastname: Grathwohl
authors.forename: Judy
authors.initials: J
authors.lastname: Halliday
authors.forename: Senka
authors.initials: S
authors.lastname: Henderson
authors.forename: Ann
authors.initials: A
authors.lastname: Lam
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Maretta
authors.initials: M
authors.lastname: Mann
authors.forename: Craig
authors.initials: C
authors.lastname: Muldoon
authors.forename: Andrew
authors.initials: A
authors.lastname: Pearson
authors.forename: Rajaratnam
authors.initials: R
authors.lastname: Premraj
authors.forename: Tracie
authors.initials: T
authors.lastname: Ramsdale
authors.forename: Tony
authors.initials: T
authors.lastname: Rossetti
authors.forename: Karl
authors.initials: K
authors.lastname: Schafer
authors.forename: Giang
authors.initials: G
authors.lastname: Le Thanh
authors.forename: Gerald
authors.initials: G
authors.lastname: Tometzki
authors.forename: Frank
authors.initials: F
authors.lastname: Vari
authors.forename: Géraldine
authors.initials: G
authors.lastname: Verquin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Waanders
authors.forename: Michael
authors.initials: M
authors.lastname: West
authors.forename: Norbert
authors.initials: N
authors.lastname: Wimmer
authors.forename: Annika
authors.initials: A
authors.lastname: Yau
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.forename: Wim
authors.initials: W
authors.lastname: Meutermans
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009005:Monosaccharides / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; C103263:MCHR1 protein, human; D009005:Monosaccharides; D009842:Oligopeptides; D017481:Receptors, Somatostatin