Τίτλος:
An evaluation of indirubin analogues as phosphorylase kinase inhibitors
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 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 et al., 2006 [20]) 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 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.
Συγγραφείς:
Begum, J.
Skamnaki, V.T.
Moffatt, C.
Bischler, N.
Sarrou, J.
Skaltsounis, A.-L.
Leonidas, D.D.
Oikonomakos, N.G.
Hayes, J.M.
Περιοδικό:
Journal of Molecular Graphics and Modelling
Εκδότης:
ELSEVIER SCIENCE INC 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Λέξεις-κλειδιά:
Cell death; Digital storage; Enzyme activity; Enzyme inhibition; Enzymes; Free energy; Ligands; Phosphorylation, Glycogen phosphorylasea; Indirubins; Kinase inhibitors; QM/MM-PBSA; Sigma-hole; Type-2 diabetes, Binding energy, 6 bromo 5 methylindirubin; 6 bromo 5 methylindirubin 3' acetoxime; 6 bromo 5 nitroindirubin 3' acetoxime; 6 bromo 5 nitroindirubin 3' oxime; 6 bromo n methylindirubin; 6 bromo n methylindirubin 3' acetoxime; 6 bromoindirubin; 6 bromoindirubin 3' acetoxime; 6 bromoindirubin 3' oxime; 6 chloroindirubin; 6 chloroindirubin 3' oxime; 6 fluoroindirubin; 6 fluoroindirubin 3' oxime; 6 iodoindirubin 3' oxime; 6 Methoxindirubin 3' acetoxime; 6 Methoxindirubin 3' oxime; 6 vinylindirubin; 6 vinylindirubin 3' acetoxime; 6 vinylindirubin 3' oxime; 6,5 dichloroindirubin 3' acetoxime; 6,5 dichloroindirubin 3' oxime; 6,6 dibromoindirubin 3' oxime; 7 bromoindirubin 3' acetoxime; 7 bromoindirubin 3' oxime; antineoplastic agent; indirubin; indirubin 3' acetoxime; indirubin 3' methoxime; indirubin 3' oxime; unclassified drug; unindexed drug; 7-bromoindirubin-3'-oxime; antidiabetic agent; CDK2 protein, human; CDK5 protein, human; cyclin dependent kinase 2; cyclin dependent kinase 5; glycogen synthase kinase 3; glycogen synthase kinase 3 alpha; glycogen synthase kinase 3 beta; indirubin; indole derivative; ligand; oxime; phosphorylase kinase; protein binding; protein kinase inhibitor, animal tissue; antineoplastic activity; Article; binding affinity; binding site; drug potency; drug screening; drug selectivity; enzyme inhibition; female; molecular docking; molecular mechanics; nonhuman; priority journal; quantum mechanics; rabbit; structure activity relation; antagonists and inhibitors; chemistry; computer interface; high throughput screening; human; molecular genetics; protein motif; protein secondary structure; protein tertiary structure; thermodynamics, Amino Acid Motifs; Binding Sites; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 5; Glycogen Synthase Kinase 3; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Indoles; Ligands; Molecular Docking Simulation; Molecular Sequence Data; Oximes; Phosphorylase Kinase; Protein Binding; Protein Kinase Inhibitors; Protein Structure, Secondary; Protein Structure, Tertiary; Structure-Activity Relationship; Thermodynamics; User-Computer Interface
DOI:
10.1016/j.jmgm.2015.07.010
