# Trustworthy Protein-Ligand Binding Affinity Prediction via Reliability-Aware Multi-Engine Fusion

arXiv: https://arxiv.org/abs/2607.17601 · HTML: https://mlsanity.com/paper/2607.17601/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 12 of its 52 references that are in the map.
- First posted on arXiv 20 Jul 2026.

## Builds on (most cited first, 12 of 12)

- [Dropout as a Bayesian Approximation: Representing Model Uncertainty in Deep Learning](https://mlsanity.com/paper/1506.02142/) (2015)
- [Simple and Scalable Predictive Uncertainty Estimation using Deep Ensembles](https://mlsanity.com/paper/1612.01474/) (2016)
- [What Uncertainties Do We Need in Bayesian Deep Learning for Computer Vision?](https://mlsanity.com/paper/1703.04977/) (2017)
- [A Simple Baseline for Bayesian Uncertainty in Deep Learning](https://mlsanity.com/paper/1902.02476/) (2019)
- [Deep Evidential Regression](https://mlsanity.com/paper/1910.02600/) (2019)
- [Scalable Variational Gaussian Process Classification](https://mlsanity.com/paper/1411.2005/) (2014)
- [EquiBind: Geometric Deep Learning for Drug Binding Structure Prediction](https://mlsanity.com/paper/2202.05146/) (2022)
- [Accelerating high-throughput virtual screening through molecular pool-based active learning](https://mlsanity.com/paper/2012.07127/) (2020)
- [Uncertainty Toolbox: an Open-Source Library for Assessing, Visualizing, and Improving Uncertainty Quantification](https://mlsanity.com/paper/2109.10254/) (2021)
- [Development and evaluation of a deep learning model for protein-ligand binding affinity prediction](https://mlsanity.com/paper/1712.07042/) (2017)
- [Trustworthy Multimodal Regression with Mixture of Normal-inverse Gamma Distributions](https://mlsanity.com/paper/2111.08456/) (2021)
- [Estimating Treatment Effects from Irregular Time Series Observations with Hidden Confounders](https://mlsanity.com/paper/2303.02320/) (2023)

## Abstract (arXiv)

Accurate protein-ligand binding affinity prediction is central to computational drug discovery, yet modern docking engines frequently disagree without indicating which prediction to trust. Consensus scoring and ensemble methods improve mean accuracy but treat all predictions identically without interpretable confidence measures or uncertainty decomposition, ignoring the chemical context of each protein-ligand pair. To address this limitation, we introduce RELIABLE-BA (RELIABiLity-aware Evidential fusion for Binding Affinity), an evidential framework for multi-engine binding affinity prediction. Our model comprises three steps: (1) modeling each engine as an evidential expert via Normal-Inverse-Gamma distributions, (2) scaling epistemic uncertainty through learned reliability from molecular context while preserving each expert's predictive mean, and (3) fusing experts through closed-form aggregation that captures both individual uncertainty and inter-engine disagreement. Experiments on the PDBBind and BDB2020+ benchmarks demonstrate competitive point prediction with substantially improved uncertainty calibration, and additional validation on the SARS-CoV-2 Mpro dataset and 5HT2A receptor demonstrates applicability to clinically relevant drug targets. Crucially, these uncertainty estimates enable reliable filtering of protein-ligand pairs, reducing prediction error by up to 25% when retaining only high-confidence pairs. To our knowledge, RELIABLE-BA is the first multi-engine binding affinity prediction framework to combine evidential fusion with context-dependent reliability, offering a principled path toward trustworthy AI-guided drug discovery. Our code is publicly available at https://github.com/yongchand/RELIABLE-BA.