Tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF) has recently been identified as an oncogene and is an important adaptor molecule involved in multiple aspects of immunity, inflammation, and bone homeostasis. A structure-based drug design approach was used to identify compounds targeting the C-terminal adaptor function of TRAF6 in complex with its binding peptide. Based on the key interactions of the peptide with TRAF6 and a filter for drug-like properties, a PubChem chemical library (~42M compounds) was screened that led to the identification of 670 structures.  Examination by two well-known docking programs, Surflex and Glide with Prime MM-GBSA re-scoring, revealed several compounds from one particular structural core that scored high with both docking methods and had consistent binding modes. A synthesis was developed for that core that would lead to a diverse set of compounds. A library of 260 structures were docked and then processed via workflow software that resulted in 29 compounds of interest after consideration of ADME type properties. Several compounds from this library have been synthesized and then tested in a split-luciferase assay to assess their TRAF6 inhibitory activity. The design and synthesis of this novel library of compounds and the results of the biological studies will be reported.

Structure-based drug design of TRAF6 inhibitors

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.