Selective targeting of muscular AMPK by structure based virtual screening

The energy-sensor AMP-activated protein kinase (AMPK) cycles between a glycogen-bound and a free state. The muscle-specific regulatory AMPKβ2 subunit carries a high affinity carbohydrate-binding module (CBM). Upon energy stress, such as exercise, AMPK localization at glycogen allows for rapid inhibition of glycogen synthesis, whereas cytosolic AMPK is capable of stimulating insulin-independent glucose uptake. By inhibition of glycogen-binding of muscular AMPK, we hypothesize to promote glycogen synthesis and glucose import, both of which are desirable processes for type 2 diabetes patients. Based on X-ray structures of AMPKβ1 and β2 CBMs, we performed a structure-based virtual ligand screen, using an established protocol that combines rigid and flexible docking. From a commercial 800,000 ligand database, we selected the best scoring 870 compounds after our in silico screen. These compounds show 81% isoform specificity and are currently being tested in vitro.