使用决策树确定hERG通道阻滞剂

Determination of hERG channel blockers using a decision tree.

作者信息

Gepp Michael M, Hutter Michael C

机构信息

Center for Bioinformatics, Saarland University, Building C7 1, P.O. Box 15 11 50, D-66041 Saarbruecken, Germany.

出版信息

Bioorg Med Chem. 2006 Aug 1;14(15):5325-32. doi: 10.1016/j.bmc.2006.03.043. Epub 2006 Apr 17.

DOI:10.1016/j.bmc.2006.03.043

PMID:16616507

Abstract

A decision tree approach for the in silico prediction of Torsade de Pointes (TdP)-causing drugs is presented. As TdP is frequently associated with QT-interval prolongation due to inhibition of the rapid activating delayed rectifier potassium channel in the heart (hERG channel), the properties of such blockers were investigated by molecular modeling and semi-empirical AM1 molecular orbital calculations. In addition, we derived a pharmacophoric SMARTS string using structural information from high affinity compounds. A corresponding search in the PubChem database identified several compounds that exhibit QT-interval prolonging activity that were not among our data set. This SMARTS string furthermore showed to be the most significant descriptor in the decision tree approach from which guidelines for the design of safe compounds are suggested.

摘要

本文提出了一种用于计算机模拟预测致尖端扭转型室速（TdP）药物的决策树方法。由于TdP常与心脏中快速激活延迟整流钾通道（hERG通道）受抑制导致的QT间期延长相关，因此通过分子建模和半经验AM1分子轨道计算研究了此类阻滞剂的性质。此外，我们利用高亲和力化合物的结构信息推导了一个药效团SMARTS字符串。在PubChem数据库中进行的相应搜索识别出了几种具有QT间期延长活性的化合物，这些化合物不在我们的数据集中。这个SMARTS字符串在决策树方法中也是最显著的描述符，据此提出了安全化合物设计指南。