title: Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors.
abstract: A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.
authors: Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia; Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD 4229, Australia.
authors: Stephanie S
authors: SS
authors: Schweiker
authors: Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia; School of Biomolecular and Physical Sciences, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia. Electronic address: w.loughlin@griffith.edu.au.
authors: Wendy A
authors: WA
authors: Loughlin
authors: School of Biomolecular and Physical Sciences, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia.
authors: Anna S
authors: AS
authors: Lohning
authors: Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia.
authors: Maria J
authors: MJ
authors: Petersson
authors: Eskitis Institute for Drug Discovery, Nathan Campus, Griffith University, Brisbane, QLD 4111, Australia.
authors: Ian D
authors: ID
authors: Jenkins
mesh_terms: D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D024981:Glycogen Phosphorylase
keywords: Fragment screening; Glycogen Phosphorylase a; Heterocycle; Molecular docking; Tetrahydropyrimidine; Thiazoline