Discovery and Design of Novel Small Molecule GSK-3 Inhibitors Targeting the Substrate Binding Site.

ABSTRACT: The serine/threonine kinase, GSK-3, is a promising drug discovery target for treating multiple pathological disorders. Most GSK-3 inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety and drug-induced resistance. In contrast, substrate competitive inhibitors (SCIs), are considered highly selective, and more suitable for clinical practice. The development of SCIs has been largely neglected in the past because the ambiguous, undefined nature of the substrate-binding site makes them difficult to design. In this study, we used our previously described structural models of GSK-3 bound to SCI peptides, to design a pharmacophore model and to virtually screen the "drug-like" Zinc database (~6.3 million compounds). We identified leadi

SUBMITTER: Rippin I 

PROVIDER: S-EPMC7698860 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature