Enhancing Hit Discovery in Virtual Screening through Absolute Protein-Ligand Binding Free-Energy Calculations.

Area of Science:

• Computational chemistry
• Drug discovery
• Biophysics

Background:

• Accurate prediction of protein-ligand binding thermodynamics is crucial for efficient drug discovery.
• Traditional methods like empirical scoring functions have limitations in accuracy.
• Absolute binding free-energy perturbation (ABFEP) offers a theoretically robust alternative.

Purpose of the Study:

• To implement and validate an accurate and reliable ABFEP method in FEP+ for drug discovery.
• To assess the performance of ABFEP in virtual screening for hit enrichment.
• To investigate the impact of protein conformational and protonation state changes on binding free energy calculations.

Main Methods:

• Implementation of ABFEP in the FEP+ software.
• Validation using eight congeneric compound series across eight protein targets.
• Application of the alchemical ion approach for charged ligands.
• Comparison of ABFEP results with experimental binding free energies and docking scores.
• Analysis of ABFEP calculations using apo vs. holo protein structures.

Main Results:

• Calculated binding free energies showed a weighted average R² of 0.55 with experimental data.
• A root-mean-square error (RMSE) of 1.1 kcal/mol was achieved after zero-point adjustment.
• Protein reorganization free energy, influenced by conformational and protonation changes, was identified as a key factor.
• ABFEP significantly improved hit rates in virtual screening applications compared to docking and metadynamics.

Conclusions:

• The validated ABFEP method in FEP+ provides accurate predictions of protein-ligand binding thermodynamics.
• ABFEP enhances hit enrichment in virtual screening, outperforming other computational methods.
• This approach facilitates more efficient hit discovery in drug development programs.