Evaluating the FEP+ protocol for predicting binding affinity of congeneric ligands towards various soluble proteins

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Structure-activity relationship (SAR) development is crucial in medicinal chemistry.
• Computational methods for scaffold optimization vary in predictive reliability.

Purpose of the Study:

• To evaluate the accuracy of the Ligand free energy perturbation (FEP+) method.
• To assess FEP+ for predicting relative binding affinities of congeneric ligands to target proteins.

Main Methods:

• Performed 34 ligand transformations across 21 soluble proteins.
• Calculated relative binding free energies using FEP+.
• Compared calculated free energies with experimental values.

Main Results:

• Achieved a mean unsigned error of 0.46 kcal mol⁻¹.
• Obtained a coefficient of determination (R²) of 0.85.
• Demonstrated high statistical significance in predictions.

Conclusions:

• FEP+ is a reliable computational tool for medicinal chemists.
• FEP+ accurately predicts relative binding free energies.
• FEP+ is valuable for SAR development in drug discovery.