title: Evaluation of novel hyphodermin derivatives as glycogen phosphorylase a inhibitors.
abstract: The lipophilicity, permeability, solubility, polar surface area and 'rule-of-five' properties were assessed, using QikProp v2.5 (Schrödinger, Inc.) and ALOGPS 2.1 calculations, for 25 Hyphodermin derivatives. These compounds obeyed the 'rule-of-five', and the calculated physicochemical values were generally within desired limits. All compounds were tested against Glycogen Phosphorylase a (GPa). Four phenyl and benzyl substituted 2-oxo-hexahydro and tetrahydrobenzo[cd]indole carboxylic acids were identified as novel inhibitors of GPa with estimated IC(50) values in the range 0.8-1.3mM. Molecular modelling of these novel inhibitors was used to obtain the main structural features of this class of molecule for future structure-activity relationship studies.
authors.affiliation: Eskitis Institute for Cell and Molecular Therapies, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia. w.loughlin@griffith.edu.au
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Loughlin
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Pierens
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Petersson
authors.forename: Luke C
authors.initials: LC
authors.lastname: Henderson
authors.forename: Peter C
authors.initials: PC
authors.lastname: Healy
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001487:Basidiomycota / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012995:Solubility; D013499:Surface Properties
chemical_list: D005663:Furans; D007527:Isoenzymes; D008055:Lipids; D009281:Naphthalenes; C529501:hyphodermin A; C516361:hyphodermin B; C529502:hyphodermin D; D024982:Glycogen Phosphorylase, Muscle Form