Validation of the alchemical transfer method for the estimation of relative binding affinities of molecular series

Sabanés Zariquiey, Francesc; Pérez, Adrià; Majewski, Maciej; Gallicchio, Emilio; De Fabritiis, Gianni

doi:http://dx.doi.org/10.1021/acs.jcim.3c00178

Validation of the alchemical transfer method for the estimation of relative binding affinities of molecular series

Citation

Sabanés Zariquiey F, Pérez A, Majewski M, Gallicchio E, De Fabritiis G. Validation of the alchemical transfer method for the estimation of relative binding affinities of molecular series. J Chem Inf Model. 2023 Apr 24;63(8):2438-44. DOI: 10.1021/acs.jcim.3c00178

Abstract

The accurate prediction of protein-ligand binding affinities is crucial for drug discovery. Alchemical free energy calculations have become a popular tool for this purpose. However, the accuracy and reliability of these methods can vary depending on the methodology. In this study, we evaluate the performance of a relative binding free energy protocol based on the alchemical transfer method (ATM), a novel approach based on a coordinate transformation that swaps the positions of two ligands. The results show that ATM matches the performance of more complex free energy perturbation (FEP) methods in terms of Pearson correlation but with marginally higher mean absolute errors. This study shows that the ATM method is competitive compared to more traditional methods in speed and accuracy and offers the advantage of being applicable with any potential energy function.