Recent Advances in Alchemical Binding Free Energy Calculations for Drug Discovery

Rigorous physics-based methods to calculate binding free energies of protein–ligand complexes have become a valued component of structure-based drug design. Relative and absolute binding free energy calculations have been deployed prospectively in support of solving diverse drug discovery challenges. Here we review recent applications of binding free energy calculations to fragment growing and linking, scaffold hopping, binding pose validation, virtual screening, covalent enzyme inhibition, and positional analogue scanning. Furthermore, we discuss the merits of using protein models and highlight recent efforts to replace costly binding free energy calculations with predictions from machine learning models trained on a limited number of free energy perturbation or thermodynamic integration calculations thereby allowing for extended chemical space exploration.