Practical application of ligand efficiency metrics in lead optimisation.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Computational Chemistry

Background:

• Composite metrics normalizing biological potency with physicochemical properties (e.g., lipophilicity) are increasingly used.
• Lack of consensus and criticisms surround the application of these metrics.
• Lead optimization in drug discovery requires robust methodologies for evaluating compound quality.

Purpose of the Study:

• To present a practical approach for applying composite metrics in lead optimization.
• To objectively discuss the principles guiding the use of these metrics.
• To illustrate the utility of lipophilic ligand efficiency (LLE) in advancing drug discovery projects.

Main Methods:

• Development and application of lipophilic ligand efficiency (LLE) as a composite metric.
• Analysis of LLE in the context of lead optimization projects.
• Derivation of heuristic guidelines for lipophilicity-based optimization.

Main Results:

• Successful application of LLE facilitated the progression of multiple drug discovery projects.
• Demonstrated the utility of LLE in guiding medicinal chemistry efforts.
• Identified key principles for effective use of lipophilicity in optimization.

Conclusions:

• The proposed approach and derived guidelines offer a framework for lipophilicity-based optimization.
• These guidelines are potentially applicable across diverse chemical series and protein targets.
• Standardized use of metrics like LLE can improve the efficiency and success rate of drug discovery.