Dr. William Metzler
Associate Director, Lead Development, Bristol-Myers Squibb

February 3, 2016
11:00 am – 12:00 pm
C-121

“Beyond Activity Measurements: Leveraging Biophysics and Structure for Hit Identification and Prioritization”

Abstract: The emergence of fragment-based screening as a vehicle for identifying novel chemical leads is challenging the current paradigm for lead optimization. When dealing with molecules with the chemical simplicity of fragments, one can no longer rely solely on potency. And while ligand efficiency (the binding energy per heavy atom) is becoming increasingly popular for evaluating the quality of hits, one often requires a more detailed understanding of the molecular interactions leading to the observed potency.   This presentation will describe our efforts to create a “biophysical toolbox” for evaluating and prioritizing hits. The toolbox contains methods for examining a compound’s propensity to aggregate, its specificity of binding, assessment of reversibility, and thermodynamic properties. Combined with the mapping of receptor:ligand interactions at the molecular level that is afforded by structural studies, the approach provides additional information for selecting hits that are the most likely to progress at a critical point in early-phase decision, thereby facilitating the delivery of high quality leads.