dc.creator | Begum, J. | en |
dc.creator | Skamnaki, V. T. | en |
dc.creator | Moffatt, C. | en |
dc.creator | Bischler, N. | en |
dc.creator | Sarrou, J. | en |
dc.creator | Skaltsounis, A. L. | en |
dc.creator | Leonidas, D. D. | en |
dc.creator | Oikonomakos, N. G. | en |
dc.creator | Hayes, J. M. | en |
dc.date.accessioned | 2015-11-23T10:23:43Z | |
dc.date.available | 2015-11-23T10:23:43Z | |
dc.date.issued | 2015 | |
dc.identifier | 10.1016/j.jmgm.2015.07.010 | |
dc.identifier.issn | 10933263 | |
dc.identifier.uri | http://hdl.handle.net/11615/26224 | |
dc.description.abstract | 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 et al., 2012 [6]). 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 IC<inf>50</inf> 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 et al., 2006 [20]) is revealed as a specific inhibitor of PhK (IC<inf>50</inf> = 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 σ-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. © 2015 Elsevier Inc. | en |
dc.source | Journal of Molecular Graphics and Modelling | en |
dc.source.uri | http://www.scopus.com/inward/record.url?eid=2-s2.0-84941356336&partnerID=40&md5=51ed5efc9cec0be0c2b69e5cd32be482 | |
dc.subject | Glycogen phosphorylasea | en |
dc.subject | Indirubins | en |
dc.subject | Kinase inhibitors | en |
dc.subject | QM/MM-PBSA | en |
dc.subject | Sigma-hole | en |
dc.subject | Type 2 diabetes | en |
dc.subject | Cell death | en |
dc.subject | Digital storage | en |
dc.subject | Enzyme activity | en |
dc.subject | Enzyme inhibition | en |
dc.subject | Enzymes | en |
dc.subject | Free energy | en |
dc.subject | Ligands | en |
dc.subject | Phosphorylation | en |
dc.subject | Type-2 diabetes | en |
dc.subject | Binding energy | en |
dc.subject | 6 bromo 5 methylindirubin | en |
dc.subject | 6 bromo 5 methylindirubin 3' acetoxime | en |
dc.subject | 6 bromo 5 nitroindirubin 3' acetoxime | en |
dc.subject | 6 bromo 5 nitroindirubin 3' oxime | en |
dc.subject | 6 bromo n methylindirubin | en |
dc.subject | 6 bromo n methylindirubin 3' acetoxime | en |
dc.subject | 6 bromoindirubin | en |
dc.subject | 6 bromoindirubin 3' acetoxime | en |
dc.subject | 6 bromoindirubin 3' oxime | en |
dc.subject | 6 chloroindirubin | en |
dc.subject | 6 chloroindirubin 3' oxime | en |
dc.subject | 6 fluoroindirubin | en |
dc.subject | 6 fluoroindirubin 3' oxime | en |
dc.subject | 6 iodoindirubin 3' oxime | en |
dc.subject | 6 Methoxindirubin 3' acetoxime | en |
dc.subject | 6 Methoxindirubin 3' oxime | en |
dc.subject | 6 vinylindirubin | en |
dc.subject | 6 vinylindirubin 3' acetoxime | en |
dc.subject | 6 vinylindirubin 3' oxime | en |
dc.subject | 6,5 dichloroindirubin 3' acetoxime | en |
dc.subject | 6,5 dichloroindirubin 3' oxime | en |
dc.subject | 6,6 dibromoindirubin 3' oxime | en |
dc.subject | 7 bromoindirubin 3' acetoxime | en |
dc.subject | 7 bromoindirubin 3' oxime | en |
dc.subject | antineoplastic agent | en |
dc.subject | indirubin | en |
dc.subject | indirubin 3' acetoxime | en |
dc.subject | indirubin 3' methoxime | en |
dc.subject | indirubin 3' oxime | en |
dc.subject | unclassified drug | en |
dc.subject | unindexed drug | en |
dc.subject | animal tissue | en |
dc.subject | antineoplastic activity | en |
dc.subject | Article | en |
dc.subject | binding affinity | en |
dc.subject | binding site | en |
dc.subject | drug potency | en |
dc.subject | drug screening | en |
dc.subject | drug selectivity | en |
dc.subject | female | en |
dc.subject | molecular docking | en |
dc.subject | molecular mechanics | en |
dc.subject | nonhuman | en |
dc.subject | priority journal | en |
dc.subject | quantum mechanics | en |
dc.subject | rabbit | en |
dc.subject | structure activity relation | en |
dc.title | An evaluation of indirubin analogues as phosphorylase kinase inhibitors | en |
dc.type | journalArticle | en |