Evaluation of novel hyphodermin derivatives as glycogen phosphorylase a inhibitors.
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.
Loughlin
Wendy A
WA
Eskitis Institute for Cell and Molecular Therapies, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia. w.loughlin@griffith.edu.au
Pierens
Gregory K
GK
Petersson
Maria J
MJ
Henderson
Luke C
LC
Healy
Peter C
PC
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
D005663:Furans; D007527:Isoenzymes; D008055:Lipids; D009281:Naphthalenes; C529501:hyphodermin A; C516361:hyphodermin B; C529502:hyphodermin D; D024982:Glycogen Phosphorylase, Muscle Form