Classifying druggability on potential binding sites of glycogen synthase kinase-3β: An in-silico assessment

Abstract

Putative binding sites of glycogen synthase kinase-3β (GSK-3β) have been identified by various computational methods; however, the druggability of these pockets is still unknown. Herein, we assessed a dataset of 24 Protein Data Bank (PDB) crystal structures of GSK-3β using SiteMap to compute the druggability of each identified site. The binding sites were assessed with two site-scoring functions known as the Druggability score (Dscore) and SiteScore (SScore) within SiteMap. An average of eight surface pockets were identified, of which pocket 1 (orthosteric site) and pocket 7 (allosteric site) exhibited ligand-binding characteristics, as analyzed by SiteScore. We further analyzed the druggability of each site with Dscore; pocket 1 proved to be a druggable site, and pocket 7 failed to meet the druggability criteria. The quantitative pocket properties of site 7 were further evaluated to identify plausible reasons for classification as a “difficult” site. In conclusion, these results accurately classified binding sites of GSK-3β.