Glycogen synthase kinase 3 beta (GSK-3�) is a serine/threonine protein kinase and has been identified as a kinase for more than forty different proteins in a variety of biological pathways. It has recently been implicated in numerous diseases such as type-II diabetes, cancers, inflammation, and neurodegenerative diseases. Previously in our group, a virtual screening was performed to identify structurally novel and diverse inhibitors of GSK-3�. This was done by pharmacophore modeling, diversity analysis, and ensemble docking. Out of 24 structurally diverse hit compounds submitted for biological evaluation, a total of 15 compounds were proven to be GSK-3� inhibitors with one lead compound possessing submicromolar inhibitory activity. This compound was chosen as the lead and was subjected to structural optimization. An in house focused combinatorial library, generated based on the lead compound, underwent conformational analysis and ensemble docking. The top ranked compounds were either purchased or synthesized depending on their commercial availability then tested in an in vitro assay. In this presentation, results from the first stage of virtual screening and the second stage of lead optimization shall be highlighted, including the generation of the ligand-based pharmacophore, focused virtual library generation, ensemble docking, and in vitro data of the identified/optimized lead compounds.

Structure-based lead optimization of a novel glycogen synthase kinase 3 beta (GSK-3�) inhibitor

248th National Meeting (2014)

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