Protein-Ligand Binding Free Energy Calculations with FEP.

Area of Science:

• Computational Biophysics
• Structure-Based Drug Design
• Molecular Dynamics Simulations

Background:

• Accurate protein-ligand binding free energy calculation is crucial for drug discovery.
• Traditional alchemical free energy perturbation (FEP) methods faced challenges: limited force field accuracy, inadequate sampling, and high computational cost.
• These limitations historically hindered the widespread application of FEP in drug discovery projects.

Purpose of the Study:

• To outline methodological advances in FEP+ technology for protein-ligand binding free energy calculations.
• To demonstrate the improved accuracy and reliability of FEP+ in drug discovery.
• To discuss extensions of FEP+ for challenging molecular transformations.

Main Methods:

• Utilized FEP+ technology, incorporating OPLS3 force fields and Replica Exchange with Solute Tempering (REST2) enhanced sampling.
• Combined REST2 sampling with conventional FEP through FEP/REST for improved simulation efficiency.
• Employed advanced simulation setup and data analysis techniques.

Main Results:

• FEP+ enables accurate and reliable prediction of protein-ligand binding free energies.
• Validated FEP+ in retrospective studies and demonstrated prospective applications in drug discovery.
• Extended FEP+ to handle complex perturbations like core-hopping and covalent inhibitor optimization.

Conclusions:

• Recent advances in FEP+ have overcome previous limitations, making it a powerful tool for drug discovery.
• FEP+ calculations are positioned to guide small-molecule drug discovery with high accuracy.
• Best practices and limitations of FEP+ methodology are examined for real-world applications.