Development of a computational model for covalent STAT3 inhibitors

Purpose and goal

The purpose and goal of this project was to generate a computer model showing how a natural product, galiellalactone, binds to the STAT3 protein. The computational chemistry model should describe and explain how galiellalactone and compounds based on galiellalactone bind to and interact with STAT3 and be used to design and optimize new compounds and also be used to find new compound classes. This could lead to new anti-cancer drugs as STAT3 is involved in the growth and malignancy of cancer cells.

Expected results and effects

A computer model explaining how galiellalactone binds to STAT3 could not be generated. The project showed the difficulties in creating models of compounds that bind covalently and clearly highlighted that alternative and complimentary methods are required for this class of compounds. However, a virtual screen against STAT3 could be performed and two new binding sites were identified and several new molecules were found as hits.

Planned approach and implementation

The project used all available information on STAT3 and STAT3 binding inhibitors. The project approach enabled the virtual screen to be performed independently of a model explaining the binding of galiellalactone to STAT3. Different software programs were evaluated and an intensive contact between the computational chemists and the medicinal chemists permitted that problems and questions could be approached from different angles. A continuation with data from the virtual screen hits and a protein structure with galiellalactone bound would be very productive.