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Rethinking Ligand Efficiency: Normalization Pitfalls, Uncertainty, and State-Invariant Metrics.

¹Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden.

ACS Medicinal Chemistry Letters

|December 17, 2025

Summary

Ligand efficiency (LE) metrics are biased by molecule size. This study introduces a new, size-independent metric to improve drug discovery efficiency and guide optimization from fragments to leads.

Keywords:

Ligand efficiency normalization standard state uncertainty

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Area of Science:

Medicinal Chemistry
Computational Chemistry
Drug Discovery

Background:

Ligand efficiency (LE) is crucial for evaluating drug candidates.
Current LE metrics exhibit a size bias, hindering accurate comparisons.
Existing size-independent metrics are sensitive to standard state choices.

Purpose of the Study:

To critically review normalization pitfalls in LE metrics.
To address uncertainty propagation in efficiency calculations.
To introduce a novel, state-invariant, size-normalized LE metric.

Main Methods:

Analysis of existing LE definitions and their mathematical properties.
Development of a new normalization strategy for LE.
Validation of the proposed metric using computational approaches.

Main Results:

Demonstration of inherent size bias in traditional LE metrics.
Identification of limitations in current size-independent LE variants.
Introduction of a robust, size-normalized, and state-invariant LE metric.

Conclusions:

The proposed metric overcomes limitations of existing LE measures.
This new metric facilitates reliable efficiency-guided optimization.
Improved LE assessment aids in the development of more effective drug leads.