45 research outputs found
An evaluation of indirubin analogues as phosphorylase kinase inhibitors
Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170 – 0.360 µM, with indirubin-3’-acetoxime (1c) the most potent. 7-bromoindirubin-3’-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting -hole effects is highlighted. A new statistical metric, the ‘sum of the modified logarithm of ranks’ (SMLR), has been defined which measures performance of a model for both the “early recognition” (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6’(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work
Glycogen phosphorylase as a molecular target for type 2 diabetes therapy
Journal URL: http://www.bentham.org/cpps
Effect of Polycarboxylates on Phosphorylase-B
Journal URL: http://www.sciencedirect.com/science/journal/0006291
Unidentified Activator of Phosphorylase-B
Journal URL: http://www.sciencedirect.com/science/journal/0968000
Sulfate Activates Phosphorylase-B by Binding to the Ser (P) Site
Journal URL: http://www.sciencedirect.com/science/journal/0167483
Crystallization of Pig Skeletal Phosphorylase-B - Purification, Physical and Catalytic Characterization
Journal URL: http://www.sciencedirect.com/science/journal/0167483
Structural basis of the synergistic inhibition of glycogen phosphorylase a by caffeine and a potential antidiabetic drug
Journal URL: http://www.sciencedirect.com/science/journal/0003986
Interaction of Aliphatic-Amines with Glycogen-Phosphorylase
Journal URL: http://jb.oxfordjournals.org