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.