Scholarlink

<p>Machine learning offers great promise for fast and accurate binding affinity predictions. However, current models lack robust evaluation and fail on tasks encountered in (hit-to-) lead optimisation, such as ranking the binding affinity of a congeneric series of ligands, thereby limiting their application in drug discovery. Here, we address these issues by first introducing a novel attention-based graph neural network model called AEV-PLIG (atomic environment vector–protein ligand interaction graph). Second, we introduce a new and more realistic out-of-distribution test set called the OOD Test. We benchmark our model on this set, CASF-2016, and a test set used for free energy perturbation (FEP) calculations, that not only highlights the competitive performance of AEV-PLIG, but provides a realistic assessment of machine learning models with rigorous physics-based approaches. Moreover, we demonstrate how leveraging augmented data (generated using template-based modelling or molecular docking) can significantly improve binding affinity prediction correlation and ranking on the FEP benchmark (weighted mean&#xa0;PCC and Kendall’s <i>τ</i> increases from 0.41 and 0.26 to 0.59 and 0.42). These strategies together are closing the performance gap with FEP calculations (FEP+ achieves weighted mean&#xa0;PCC and Kendall’s <i>τ</i> of 0.68 and 0.49 on the FEP benchmark) while being &#xa0;~400,000 times faster.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Narrowing the gap between machine learning scoring functions and free energy perturbation using augmented data

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月8日

查看全文
  • Ísak Valsson,
  • Matthew T. Warren,
  • Charlotte M. Deane,
  • Aniket Magarkar,
  • Garrett M. Morris,
  • Philip C. Biggin

摘要

Machine learning offers great promise for fast and accurate binding affinity predictions. However, current models lack robust evaluation and fail on tasks encountered in (hit-to-) lead optimisation, such as ranking the binding affinity of a congeneric series of ligands, thereby limiting their application in drug discovery. Here, we address these issues by first introducing a novel attention-based graph neural network model called AEV-PLIG (atomic environment vector–protein ligand interaction graph). Second, we introduce a new and more realistic out-of-distribution test set called the OOD Test. We benchmark our model on this set, CASF-2016, and a test set used for free energy perturbation (FEP) calculations, that not only highlights the competitive performance of AEV-PLIG, but provides a realistic assessment of machine learning models with rigorous physics-based approaches. Moreover, we demonstrate how leveraging augmented data (generated using template-based modelling or molecular docking) can significantly improve binding affinity prediction correlation and ranking on the FEP benchmark (weighted mean PCC and Kendall’s τ increases from 0.41 and 0.26 to 0.59 and 0.42). These strategies together are closing the performance gap with FEP calculations (FEP+ achieves weighted mean PCC and Kendall’s τ of 0.68 and 0.49 on the FEP benchmark) while being  ~400,000 times faster.