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Three-dimensional structure-activity relationships of drugs induced cardiovascular side effects (prolongation in the QT interval)

药物引起的心血管副作用（QT间期延长）的三维构效关系

基本信息

批准号：
15590048
负责人：
HIRONO Shuichi
金额：
$ 2.3万
依托单位：
School of Pharmaceutical sciences, Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

1 To estimate the active conformation of drugs whose active conformations are difficult to obtain from the experimental approach, we developed the two computer programs, the CAMDAS program for a conformational analysis and the molecular superposing program. The CAMDAS is an automated conformational sampling program using molecular dynamics. The molecular superposing program aims at overlaying two molecules based on the physicochemical properties of the atomic groups in a molecule. We already reported that the method combined two procedures are useful for elucidating a pharmacophore and find the active conformation among a lot of conformations of a drug. In this study, we applied the method to investigate drugs which have side effects that prolongs QT interval. We carried out the CAMDAS calculation and the molecular superposing for those drug and estimated the active conformation and the pharmacophore with respect to the prolongation effect in the QT interval.2 Potassium channel, I_<kr> participates in the prolongation effect in the QT interval. Ikr consists of HERG and MiRP1. A pore domain of I_<kr> exists in HERG. Three dimensional structure of one of the potassium channel, KcsA is clear in Xray crystal analysis. Then the three dimensional structure model of the pore domain of HERG was created with homology modeling program (FAMS) using the KcsA as the reference structure. Energy minimized calculation of the model was performed to obtain the pore model using SYBYL. We searched for the ligand binding region on the pore model using HBOP utilized the hydrophobic potential. The binding conformation of ligand was made to docking to binding the region using Unity3D program and finally the HERG-ligand complex model was created.

1 为了估计活性构象难以通过实验方法获得的药物的活性构象，我们开发了两个计算机程序，用于构象分析的 CAMDAS 程序和分子叠加程序。 CAMDAS 是一种利用分子动力学的自动构象采样程序。分子叠加程序旨在根据分子中原子团的物理化学性质叠加两个分子。我们已经报道过，该方法结合了两个过程，可用于阐明药效团并在药物的许多构象中找到活性构象。在这项研究中，我们应用该方法来研究具有延长QT间期副作用的药物。我们对这些药物进行了CAMDAS计算和分子叠加，并估计了与QT间期延长作用相关的活性构象和药效团。2钾通道I_<kr>参与了QT间期延长作用。 Ikr 由 HERG 和 MiRP1 组成。 HERG 中存在 I_<kr> 的孔结构域。钾通道之一 KcsA 的三维结构在 X 射线晶体分析中清晰可见。然后以KcsA为参考结构，利用同源建模程序（FAMS）创建HERG孔域的三维结构模型。使用SYBYL对模型进行能量最小化计算以获得孔隙模型。我们利用HBOP利用疏水势在孔模型上寻找配体结合区域。利用Unity3D程序将配体的结合构象对接至结合区域，最终建立HERG-配体复合物模型。