An evaluation of indirubin analogues as phosphorylase kinase inhibitors

摘要: 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, few reported structural studies on PhK inhibitors, this hinders structure based drug design approach. In study, the inhibitory potential 38 indirubin analogues have investigated. 11 these ligands had IC50 values in range 0.170-0.360μM, indirubin-3'-acetoxime (1c) most potent. 7-Bromoindirubin-3'-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas 2006 [20]) is revealed specific inhibitor (IC50=1.8μM). Binding assay experiments performed using both PhK-holo PhK-γtrnc confirmed effects to arise from binding at domain (γ subunit). High level computations QM/MM-PBSA free energy calculations were good agreement experimental data, determined statistical analysis, support ATP-binding site. The value QM description for halogenated exhibiting σ-hole highlighted. A new metric, 'sum modified logarithm ranks' (SMLR), defined measures performance model "early recognition" (ranking earlier/higher) active compounds their relative ordering by potency. Through detailed activity relationship analysis considering other kinases (CDK2, CDK5 GSK-3α/β), 6'(Z) 7(L) substitutions identified achieve selective inhibition. key site residues involved can also be targeted ligand scaffolds future work.