Rethinking Ligand Efficiency: Normalization Pitfalls, Uncertainty, and State-Invariant Metrics
Year: 2025
Type: editorial
Abstract: Ligand efficiency (LE), defined as the negative binding free energy per heavy atom, is a widely used metric in medicinal chemistry. Yet its mathematical construction embeds a strong size bias that distorts cross-size comparisons, and size-independent variants inherit sensitivity to the arbitrary choice of standard state. This study reviews normalization pitfalls, addresses uncertainty propagation, and introduces a state-invariant, size-normalized metric for efficiency-guided optimization from fragments to leads.
Source: ACS Medicinal Chemistry Letters
Author: Hongtao Zhao
Institution: AstraZeneca (Sweden)
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4416129456