Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Early stage drug discovery in the australian cancer research foundation rational drug discovery centre (#236)

Brendan W Stevenson , Jessica K Holien , Michael A Gorman , Belamy B Cheung , Glenn M Marshall , Michael W Parker

The Australian Cancer Research Foundation Rational Drug Discovery Centre is built around four nodes: high throughput insect/mammalian cell expression, protein interactions (surface plasmon resonance, isothermal calorimetry, X-ray crystallography), molecular modelling/virtual screening and imaging (FACS, micro CT, laser scanning cytometry). Generally, a drug discovery project will begin with the virtual screening of druggable pockets located in the 3-dimensional structure of the target protein (X-ray or homology model). The druggable pockets are explored using an in-house small molecule library of ~6.5 million drug-like compounds. A “hit list” of lead drug-like compounds is then purchased for biological screening (in vitro and in vivo assays). Compounds with biological activity for the target protein are further explored using in-silico 2D similarity searching methods, surface plasmon resonance and isothermal calorimetry. A medicinal chemistry program is undertaken once clear structure-activity-relationships are established for the compound series. We have applied our methodology, with some success, to traditional protein targets (protein kinases, detoxifying enzymes and membrane-associating proteins such as GPCRs), fragment screening, and the discovery of small molecule regulators of protein-protein interactions. In addition, more than one hundred crystal structures have been determined. This combinatorial approach to drug discovery has been applied to various fields of medical research, including infectious disease, neurodegeneration and cancer, as presented here.