多引擎预测结合可靠性评估,提升药物靶点亲和力预测可信度。
Trustworthy Protein-Ligand Binding Affinity Prediction via Reliability-Aware Multi-Engine Fusion

- 用证据融合框架建模各对接引擎,识别不确定性来源。
- 根据分子环境动态调整置信度,高置信对子可降低25%误差。
- 适合需可靠预测的临床药物靶点研究,支持可解释决策。
准确预测蛋白质-配体结合亲和力是计算药物发现的核心,但现代对接工具常产生不一致结果且无法判断可信度。现有共识与集成方法虽提升平均精度,却未区分预测可靠性,缺乏可解释的置信度或不确定性分解,忽视了每个蛋白-配体对的化学背景。为此,我们提出RELIABLE-BA(RELIABiLity-aware Evidential fusion for Binding Affinity),一种基于证据理论的多引擎结合亲和力预测框架。模型包含三步:(1) 通过正态逆伽马分布将各引擎视为证据专家;(2) 根据分子上下文学习可靠性,调节认知不确定性,同时保留各专家的预测均值;(3) 通过闭式聚合融合专家,捕捉个体不确定性和引擎间分歧。在PDBBind和BDB2020+基准测试中表现优异,不确定性校准显著提升;在SARS-CoV-2 Mpro和5HT2A受体数据集上验证其在临床相关靶点上的适用性。关键的是,该不确定性估计可有效筛选高可信配对,仅保留高置信样本时,预测误差最高降低25%。据我们所知,RELIABLE-BA是首个将证据融合与上下文依赖可靠性结合的多引擎亲和力预测框架,为可信的AI驱动药物发现提供系统路径。代码已公开于https://github.com/yongchand/RELIABLE-BA。
原文摘要 · Abstract (English)
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.
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