Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors

Eur J Med Chem. 2014 Sep 12:84:584-94. doi: 10.1016/j.ejmech.2014.07.063. Epub 2014 Jul 19.

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.

Keywords: Fragment screening; Glycogen Phosphorylase a; Heterocycle; Molecular docking; Tetrahydropyrimidine; Thiazoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Phosphorylase / antagonists & inhibitors*
  • Glycogen Phosphorylase / metabolism
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Liver / enzymology
  • Molecular Docking Simulation*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Glycogen Phosphorylase