<br/>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 corehops, linker replacements, R-group optimizations and macrocyclization approaches that generate designs with a given conformational profile to enhance the likelihood of maintaining or improving potency. We then 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 also highlight cases where docking scores alone are insufficient to predict compound potency and how combining in silico enumeration and rigorous profiling strategies can accelerate drug discovery efforts.

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

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.