Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery.

Abstract

Computational methods constitute efficient strategies for screening and optimizing potential drug molecules. A critical factor in this process is the binding affinity between candidate molecules and targets, quantified as binding free energy. Among various estimation methods, alchemical transformation methods stand out for their theoretical rigor. Despite challenges in force field accuracy and sampling efficiency, advancements in algorithms, software, and hardware have increased the application of free energy perturbation (FEP) calculations in the pharmaceutical industry. Here, we review the practical applications of FEP in drug discovery projects since 2018, covering both ligand-centric and residue-centric transformations. We show that relative binding free energy calculations have steadily achieved chemical accuracy in real-world applications. In addition, we discuss alternative physics-based simulation methods and the incorporation of deep learning into free energy calculations.