English

Attribution Methods Reveal Flaws in Fingerprint-Based Virtual Screening

Biomolecules 2020-07-10 v2 Quantitative Methods

Abstract

Fingerprint-based models for protein-ligand binding have demonstrated outstanding success on benchmark datasets; however, these models may not learn the correct binding rules. To assess this concern, we use in silico datasets with known binding rules to develop a general framework for evaluating model attribution. This framework identifies fragments that a model considers necessary to achieve a particular score, sidestepping the need for a model to be differentiable. Our results confirm that high-performing models may not learn the correct binding rule, and suggest concrete steps that can remedy this situation. We show that adding fragment-matched inactive molecules (decoys) to the data reduces attribution false negatives, while attribution false positives largely arise from the background correlation structure of molecular data. Normalizing for these background correlations helps to reveal the true binding logic. Our work highlights the danger of trusting attributions from high-performing models and suggests that a closer examination of fingerprint correlation structure and better decoy selection may help reduce misattributions.

Keywords

Cite

@article{arxiv.2007.01436,
  title  = {Attribution Methods Reveal Flaws in Fingerprint-Based Virtual Screening},
  author = {Vikram Sundar and Lucy Colwell},
  journal= {arXiv preprint arXiv:2007.01436},
  year   = {2020}
}

Comments

4 pages, 5 figures. In proceedings for the 2020 ICML workshop on Machine Learning Interpretability for Scientific Discovery

R2 v1 2026-06-23T16:49:03.612Z