Protein-protein interactions (PPIs) play a pivotal role in all biological processes and their dysregulation is associated with multiple diseases. For over 20 years this target class was considered ‘undruggable’ by small molecule therapeutics. The cancer drug venetoclax was the first successful oral small molecule drug reaching approval, despite violating one or more ‘drug-likeness’ guidelines: its high MW and lipophilicity were required to bind the large flat lipophilic binding site on B-cell lymphoma-2 (Bcl-2) to disrupt its interaction with another protein, BH3. This and other emerging examples suggest that the structural requirements for optimal biophysical and physical chemistry properties of small molecule PPI inhibitors may be interrelated. In order to explore this hypothesis, we examined Structure-Activity and Property Relationships of Mcl-1 and RASG12C leads using X-ray protein-ligand complexes and experimental free drug solution conformations. We found that the structural insights obtained for optimal pharmacological activity also inform enhanced ligand structure-based design of physicochemical properties of orally bioavailable drug candidates, providing a rational design paradigm to accelerate future PPI drug discovery.

Role of solution conformations in structure-based design of intracellular PPI inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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