论文标题
使用拓扑Laplacian辅助AI模型对HERG阻滞剂的药品银行数据库进行虚拟筛选
Virtual screening of DrugBank database for hERG blockers using topological Laplacian-assisted AI models
论文作者
论文摘要
人{\ it Ether-a-go-go}（herg）钾频道（k $ _ \ text {v} 11.1 $）在介导心脏动作潜力中起着至关重要的作用。该离子通道的封锁可能导致致命疾病和/或长QT综合征。由于其严重的HERG-抗毒性，许多药物被撤回。在毒品发现的早期阶段评估HERG封锁活动至关重要。考虑到许多药物银行化合物已被批准用于治疗治疗或具有很高的可能成为药物的潜力，我们对药品银行数据库中收集的化合物的HERG-核毒性特别感兴趣。基于机器学习的计算机工具提供了一个快速且经济的平台，用于筛选药品库化合物。我们为阻滞剂/非阻滞剂设计准确，健壮的分类器，然后构建回归器，以定量分析HERG通道上药品银行化合物的结合效力。分子序列嵌入了两种自然语言处理（NPL）方法，即自动编码器和变压器。互补的三维（3D）分子结构嵌入了两种先进的数学方法，即拓扑拉普拉西亚和代数图。借助我们最先进的工具，我们透露，在8641种药品银行中，有227种是潜在的HERG阻滞剂，这表明严重的药物安全问题。我们的预测为进一步的药物银行化合物的HERG-核毒性提供了指导。
The human {\it ether-a-go-go} (hERG) potassium channel (K$_\text{v}11.1$) plays a critical role in mediating cardiac action potential. The blockade of this ion channel can potentially lead fatal disorder and/or long QT syndrome. Many drugs have been withdrawn because of their serious hERG-cardiotoxicity. It is crucial to assess the hERG blockade activity in the early stage of drug discovery. We are particularly interested in the hERG-cardiotoxicity of compounds collected in the DrugBank database considering that many DrugBank compounds have been approved for therapeutic treatments or have high potential to become drugs. Machine learning-based in silico tools offer a rapid and economical platform to virtually screen DrugBank compounds. We design accurate and robust classifiers for blockers/non-blockers and then build regressors to quantitatively analyze the binding potency of the DrugBank compounds on the hERG channel. Molecular sequences are embedded with two natural language processing (NPL) methods, namely, autoencoder and transformer. Complementary three-dimensional (3D) molecular structures are embedded with two advanced mathematical approaches, i.e., topological Laplacians and algebraic graphs. With our state-of-the-art tools, we reveal that 227 out of the 8641 DrugBank compounds are potential hERG blockers, suggesting serious drug safety problems. Our predictions provide guidance for the further experimental interrogation of DrugBank compounds' hERG-cardiotoxicity .
