Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects

Area of Science:

• Computational chemistry
• Drug discovery and development
• Biophysics

Background:

• Accurate prediction of binding affinity is crucial for pharmaceutical research.
• Physics-based free energy calculations offer a rigorous approach to estimate binding affinity.
• Previous retrospective studies have shown the potential of these methods.

Purpose of the Study:

• To present the results of a large-scale prospective application of the Free Energy Perturbation (FEP+) method.
• To evaluate FEP+ performance in active drug discovery projects within an industrial setting.
• To compare prospective data with results from a new public benchmark dataset.

Main Methods:

• Prospective application of the FEP+ computational method.
• Utilized in active drug discovery projects at Merck KGaA.
• Comparison against a diverse, public benchmark dataset of eight pharmaceutically relevant targets.

Main Results:

• Demonstrated the application of FEP+ in real-life drug discovery scenarios.
• Provided insights into the practical challenges encountered when using free energy calculations.
• Identified limitations of current methods for future development.

Conclusions:

• Free energy calculations, specifically FEP+, have potential in industrial drug discovery.
• Real-world application highlights challenges and areas for methodological improvement.
• A new public dataset is provided to facilitate further research and benchmarking.