title: Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads.
abstract: Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC(50) values of 3.2 and 4.1 μM. Synthetic exploration of hit 59 (IC(50)=4.1 μM) yielded 25 lead inhibitors with the best illustrating IC(50) of 3.0 μM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts.
authors.affiliation: Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science University, Amman, Jordan.
authors.forename: Maha
authors.initials: M
authors.lastname: Habash
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D003198:Computer Simulation; D057225:Data Mining; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D012984:Software; D013386:Succinates / Q000737:chemistry
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; D013386:Succinates; D024981:Glycogen Phosphorylase