Hirayama Noriaki
Institute of Advanced Biosciences, Tokai University, 4-1-1 Kita-kaname, Hiratsuka, Kanagawa, 259-1292, Japan.
Drug Metab Pharmacokinet. 2017 Feb;32(1):31-39. doi: 10.1016/j.dmpk.2016.10.002. Epub 2016 Oct 18.
Idiosyncratic drug toxicities (IDTs) caused by certain drugs are a significant cause of morbidity and mortality for patients. As IDTs are not normally detected even during clinical trials, it is difficult to foresee the risk during the early stage of drug development. Prediction of potential IDTs at the earliest possible opportunity is highly desirable. The strong associations between a particular IDT and a specific human leukocyte antigen (HLA) have been reported and the recent study has disclosed that the direct interaction between a drug in question and the HLA molecule triggers the onset of IDT. Since computational method, especially docking simulation, is applicable to prediction of the binding mode and affinity between the molecules involved in the interaction, it can be used to understand the molecular mechanism of this specific type of drug toxicity. The aim of this review is firstly to outline the methodologies used for docking simulation between drug and HLA molecules. Secondary, an overview of studies on docking simulations between IDT-inducing drugs and the corresponding HLA molecules is given. The results demonstrate that docking simulations are promising to predict the molecular mechanisms of HLA-associated IDTs and point out the causative compounds derived from the relevant drug molecules.
某些药物引起的特异质性药物毒性（IDTs）是患者发病和死亡的重要原因。由于即使在临床试验期间通常也检测不到IDTs，因此在药物开发的早期阶段很难预见风险。尽早预测潜在的IDTs是非常必要的。已经报道了特定IDT与特定人类白细胞抗原（HLA）之间的强关联，并且最近的研究表明，所讨论的药物与HLA分子之间的直接相互作用触发了IDT的发作。由于计算方法，特别是对接模拟，适用于预测相互作用中涉及的分子之间的结合模式和亲和力，因此它可用于理解这种特定类型药物毒性的分子机制。这篇综述的目的首先是概述用于药物与HLA分子对接模拟的方法。其次，对诱导IDT的药物与相应HLA分子之间的对接模拟研究进行了概述。结果表明，对接模拟有望预测与HLA相关的IDTs的分子机制，并指出相关药物分子衍生的致病化合物。
