The nature of ligand efficiency

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Biophysics

Background:

• Ligand efficiency (LE) is a common metric in drug discovery, correlating binding affinity with molecular size.
• Current LE calculations are sensitive to the concentration units used for affinity, leading to inconsistent interpretations.
• The logarithmic nature of affinity measurements complicates the physical meaningfulness of LE as a direct metric.

Purpose of the Study:

• To critically evaluate the physical meaningfulness of ligand efficiency (LE) as a drug design parameter.
• To address the non-trivial dependency of LE on concentration units.
• To propose an alternative, physically sound method for normalizing affinity by molecular size.

Main Methods:

• Analysis of the physicochemical basis of ligand efficiency and its dependence on concentration units.
• Examination of group efficiency and fit quality from a physicochemical perspective.
• Development and illustration of a novel approach focusing on the direct relationship between affinity and molecular size.

Main Results:

• Ligand efficiency (LE) is shown to be not physically meaningful due to its inherent dependence on concentration units.
• The study demonstrates how to eliminate this unit-dependency by defining efficiency based on affinity's sensitivity to molecular size.
• An alternative method for normalizing affinity with respect to molecular size is presented and validated.

Conclusions:

• Ligand efficiency (LE) is an unreliable metric due to its dependence on arbitrary concentration units.
• A direct examination of the relationship between affinity and molecular size offers a more robust approach in drug discovery.
• The proposed alternative method provides a physically meaningful way to assess ligand performance relative to size.