Begum, Jaida, Skamnaki, Vassiliki T., Moffatt, Colin, Bischler, Nicolas, Sarrou, Josephine, Skaltsounis, Alexios-Leandros, Leonidas, Demetres D., Oikonomakos, Nikos G. and Hayes, Joseph (2015) An evaluation of indirubin analogues as phosphorylase kinase inhibitors. Journal of Molecular Graphics and Modelling, 61 . pp. 231-242. ISSN 10933263
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Official URL: http://dx.doi.org/10.1016/j.jmgm.2015.07.010
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.
|Uncontrolled Keywords (separate with ;):||indirubins; sigma-hole; type 2 diabetes; kinase inhibitors; glycogen phosphorylase|
|Subjects:||Physical sciences > Chemistry|
|Schools:||Faculty of Science and Technology > School of Physical Sciences and Computing|
|Deposited By:||Nuala Jones|
|Deposited On:||15 Feb 2016 14:40|
|Last Modified:||24 Oct 2016 03:06|
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