Thiazolidinedione-based PI3K alpha inhibitors: an analysis of biochemical and virtual screening methods

Jo-Anne Pinson, Oleg Schmidt-Kittler, Jiuxiang Zhu, Ian Jennings, Ken Kinzler, Bert Vogelstein, David Chalmers, Philip Thompson

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

A series of synthesized and commercially available compounds were assessed against PI3K alpha for in vitro inhibitory activity and the results compared to binding calculated in silico. Using published crystal structures of PI3K gamma and PI3K delta co-crystallized with inhibitors as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. On the other hand, PI3K alpha in the apo-form, modeled by induced fit docking, or built as a homology model gave only poor results. A PI3K alpha homology model derived from a ligand-bound PI3K delta crystal structure was developed that has a good ability to identify active compounds. The docking results identified binding poses for active compounds that differ from those identified to date and can contribute to our understanding of structure-activity relationships for PI3K inhibitors.
Original languageEnglish
Pages (from-to)514 - 522
Number of pages9
JournalChemMedChem
Volume6
Issue number3
DOIs
Publication statusPublished - 2011

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