论文标题

精确,可靠且可解释的溶解度预测具有注意力集和贝叶斯学习的药物状分子

Accurate, reliable and interpretable solubility prediction of druglike molecules with attention pooling and Bayesian learning

论文作者

Ryu, Seongok, Lee, Sumin

论文摘要

在药物发现中,水溶性是一种重要的药代动力学特性,会影响药物的吸收和分析。因此,在溶解性预测中,已经研究了其在虚拟筛选和铅优化方面的效用。最近,使用实验数据的机器学习(ML)方法很受欢迎,因为基于物理学的方法(例如量子力学和分子动力学)由于其计算成本而不适合高通量任务。但是,ML方法可以在数据缺陷条件下表现出过度拟合的问题,而大多数化学性质数据集就是这种情况。此外,ML方法被认为是黑匣子函数,因为很难解释隐藏特征对输出的贡献,阻碍了结构活性关系的分析和修改。为了解决上述问题,我们使用了自我发项式读数层开发了贝叶斯图神经网络(GNN)。与大多数在节点更新中使用自我注意力的GNN不同,在读取层上应用的自我发项会使模型能够提高预测性能并确定原子的重要性,这可以帮助引导优化,例如三种FDA批准的药物的例证。此外,贝叶斯推论使我们能够根据溶解度预测任务的不确定性分离或多或少准确的结果,我们期望我们的准确,可靠和可解释的模型可用于更仔细的决策和在药物开发中的各种应用。

In drug discovery, aqueous solubility is an important pharmacokinetic property which affects absorption and assay availability of drug. Thus, in silico prediction of solubility has been studied for its utility in virtual screening and lead optimization. Recently, machine learning (ML) methods using experimental data has been popular because physics-based methods like quantum mechanics and molecular dynamics are not suitable for high-throughput tasks due to its computational costs. However, ML method can exhibit over-fitting problem in a data-deficient condition, and this is the case for most chemical property datasets. In addition, ML methods are regarded as a black box function in that it is difficult to interpret contribution of hidden features to outputs, hindering analysis and modification of structure-activity relationship. To deal with mentioned issues, we developed Bayesian graph neural networks (GNNs) with the self-attention readout layer. Unlike most GNNs using self-attention in node updates, self-attention applied at readout layer enabled a model to improve prediction performance as well as to identify atom-wise importance, which can help lead optimization as exemplified for three FDA-approved drugs. Also, Bayesian inference enables us to separate more or less accurate results according to uncertainty in solubility prediction task We expect that our accurate, reliable and interpretable model can be used for more careful decision-making and various applications in the development of drugs.

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