Accurate binding affinity prediction (BAP) is crucial to structure-based drug design. We present [Formula: see text], a novel, generalizable machine learning algorithm for BAP that exploits recent advances in computational topology. Compared to current binding affinity prediction algorithms, [Formula: see text] shows similar or better accuracy and is more generalizable across orthogonal datasets. [Formula: see text] is not only one of the most accurate algorithms for BAP, it is also the first algorithm that is inherently interpretable. Interpretability is a key factor of trust for an algorithm and alongside generalizability, allows [Formula: see text] to be trusted in critical applications, such as inhibitor design. We visualized the features captured by [Formula: see text] for two clinically relevant protein-ligand complexes and find that [Formula: see text] captures binding-relevant structural mutations that are corroborated by biochemical data. Our work also sheds light on the features captured by current computational topology BAP algorithms that contributed to their high performance, which have been poorly understood. [Formula: see text] also offers an improvement of [Formula: see text] in computational complexity and is empirically over 10 times faster than the dominant (uninterpretable) computational topology algorithm for BAP. Based on insights from [Formula: see text], we built [Formula: see text], a scoring function for differentiating between binders and non-binders that has outstanding accuracy against 11 current algorithms for BAP. In summary, we report progress in a novel combination of interpretability, speed, and accuracy that should further empower topological screening of large virtual inhibitor libraries to protein targets, and allow binding affinity predictions to be understood and trusted. The source code for [Formula: see text] and [Formula: see text] are released open-source as part of the osprey protein design software package.
Copyright: © 2025 Long, Donald. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.