Validation of the Alchemical Transfer Method for the Estimation of Relative Binding Affinities of Molecular Series

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 pe...

Full description

Saved in:
Bibliographic Details
Published in:Journal of chemical information and modeling 2023-04, Vol.63 (8), p.2438-2444
Main Authors: Sabanés Zariquiey, Francesc, Pérez, Adrià, Majewski, Maciej, Gallicchio, Emilio, De Fabritiis, Gianni
Format: Article
Language:English
Subjects:
Affinity
Binding
Computational Chemistry
Coordinate transformations
Entropy
Free energy
Ligands
Molecular Dynamics Simulation
Performance evaluation
Perturbation
Potential energy
Protein Binding
Reproducibility of Results
Thermodynamics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.3c00178