General Theory of Fragment Linking in Molecular Design: Why Fragment Linking Rarely Succeeds and How to Improve Outcomes.

Linking two fragments binding in nearby subpockets together has become an important technique in fragment-based drug discovery to optimize the binding potency of fragment hits. Despite the expected favorable translational and orientational entropic contribution to the binding free energy of the linked molecule, brute force enumeration of chemical linker for linking fragments is rarely successful, and the vast majority of linked molecules do not exhibit the expected gains of binding potency. In this paper, we examine the physical factors that contribute to the change of binding free energy from fragment linking and develop a method to rigorously calculate these different physical contributions.

Is Structure-Based Drug Design Ready for Selectivity Optimization?

Alchemical free-energy calculations are now widely used to drive or maintain potency in small-molecule lead optimization with a roughly 1 kcal/mol accuracy. Despite this, the potential to use free-energy calculations to drive optimization of compound selectivity among two similar targets has been relatively unexplored in published studies. In the most optimistic scenario, the similarity of binding sites might lead to a fortuitous cancellation of errors and allow selectivity to be predicted more accurately than affinity.