Abstract
Glycogen synthase kinase-3β (GSK3β) is associated with various key biological processes, and it has been considered as a critical therapeutic target for the treatment of many diseases. However, it is a big challenge to develop ATP-competition GSK3β inhibitors because of the high sequence homology with other kinases. In this work, a novel parallel virtual screening strategy based on multiple GSK3β protein structures, integrating molecular docking, complex-based pharmacophore, and naive Bayesian classification, was developed to screen a large chemical database, the 50 compounds with top-scores then underwent a luminescent kinase assay, which led to the discovery of two GSK3β inhibitor hits. The high screening enrichment rate indicates the reliability and practicability of the integrated protocol. Finally, molecular docking and molecular dynamics simulation were employed to investigate the binding modes of the GSK3β inhibitors, and some “hot residues” critical to GSK3β affinity were highlighted. The present study may provide some valuable guidance for the development of novel GSK3β inhibitors.
Highlights
Glycogen synthase kinase-3 (GSK3) is an evolutionarily very conserved serine/threonine kinase that is ubiquitous in mammalian eukaryotic cells, and it presents a broad spectrum of cellular functions, like cell division, differentiation, transcription, apoptosis, and so on (Frame and Cohen, 2001; Hu et al, 2018)
The nonduplicated Glycogen synthase kinase-3b (GSK3b) inhibitors with definite biological activity were obtained from the BindingDB database (Liu et al, 2007), and the non-inhibitors were randomly selected from the ChemDiv database through the Find Diverse Molecules module in Discovery Studio 3.5 (DS3.5), and the ratio of non-inhibitors versus inhibitors was set to 1:20
The scaffold3 generated no pScore and the inDrug result is “False”. These results indicate Cpd49 would be a GSK3b selective inhibitor
Summary
Glycogen synthase kinase-3 (GSK3) is an evolutionarily very conserved serine/threonine kinase that is ubiquitous in mammalian eukaryotic cells, and it presents a broad spectrum of cellular functions, like cell division, differentiation, transcription, apoptosis, and so on (Frame and Cohen, 2001; Hu et al, 2018). GSK3b inhibitors can be roughly classified into two categories: non-ATP competition and ATP competition inhibitors (Force and Woodgett, 2009; Swinney et al, 2016; Dey et al, 2017; Saura et al, 2017). These two types of inhibitors represent two different focuses on the development of GSK3b inhibitors: affinity and selectivity. GSK3b show a 98% sequence identity to GSK3a, besides, GSK3b share a highly conserved sequence in many other kinases, such as cyclin-dependent kinases (CDK) (Bax et al, 2001), that makes it challenging to develop selective GSK3b inhibitors. The application of appropriate methods for developing high selective GSK3b inhibitors has become critical and urgent
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