In small-molecule drug discovery campaigns, the dimensions and plasticity of binding pockets define the conformational space that is accessible to successful, potent inhibitors. Here, we describe several enumeration strategies, including synthetically-accessible core transformations, R-group optimizations and macrocyclization approaches that generate designs with a given conformational profile to enhance the likelihood of maintaining or improving potency. We demonstrate how free energy methods are employed to predict the relative potency of these design ideas and provide insight into how various protein-ligand and intraligand contributions can be balanced to achieve potency. We present two case studies of how in silico enumerations and rigorous profiling strategies can accelerate drug discovery efforts.

Exerting conformational control in large-scale library enumerations and compound prioritization in drug discovery campaigns

ACS Spring Meeting 2021

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