For a given series, Ligand Efficiency (LE) can be used as a metric in drug discovery to evaluate the binding energy of a ligand relative to its size. It’s typically expressed as the binding free energy per non-hydrogen atom. Increasing molecular size increases affinity through increased interactions, however, it may also I) reduce solubility, II) lead to non-specific binding, III) increase clearance. Beyond a certain point, an increase in size also has diminished returns due to higher desolvation costs. As such, it is recommended that an increase in size should be associated with an increase in binding affinity appropriate for the binding pocket.
Importance in Computational Drug Discovery:
- Enables fair comparison of binding affinities across molecules of varying sizes within a given series, avoiding bias toward larger ligands.
- Guides fragment-based drug discovery by identifying small, efficient binders as starting points for optimization.
- Supports lead optimization by balancing potency with molecular size, reducing the risk of poor pharmacokinetics.
- Facilitates virtual screening and ranking of hits by integrating efficiency metrics into scoring functions.
- Avoids unnecessary molecular complexity during hit-to-lead and lead optimization phases.
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