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Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin.

Abstract：

:Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Bidon-Chanal A,Fuertes A,Alonso D,Pérez DI,Martínez A,Luque FJ,Medina M

doi

10.1016/j.ejmech.2012.12.014

subject

Has Abstract

pub_date

2013-02-01 00:00:00

pages

479-89

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(12)00736-2

journal_volume

60

pub_type

杂志文章

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