Many human diseases involve dysregulated states of metabolic enzymes that perturb normal physiology at the cellular level. Understanding and targeting these metabolic outliers using small molecules has proven to be a successful therapeutic strategy. However, the pathogenic nature of the loss of function mutations or complex kinetic profile of dysregulated enzyme states can pose unprecedented challenges to hit identification efforts. Fragment based approaches provide intrinsic advantages in efficiently probing the cryptic druggable pockets. Exploring multiple conformational states by parallel biophysical and biochemical screening methods are key to success in discovering relevant fragment hits. To address these needs we have strategized and implemented a comprehensive fragment library with a fit for purpose design suitable for multiple screening methods. We have successfully used intelligently pooled libraries for high-content ligand observed NMR screening with serial STD, WaterLOGSY, CPMG, DLB acquisitions, surface plasmon resonance (SPR), a variety of mass spectrometry based techniques (affinity chromatography, ultrafiltration) and X-ray crystallography to discover hits to challenging metabolic enzyme targets. Lessons learned from a few case studies will be presented.

Strategizing fragment libraries and screening methods for hit identification against metabolic enzyme targets

256th National Meeting (2018)

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