Estimation of the three-dimensional pharmacophore of ligands for rat multidrug-resistance-associated protein 2 using ligand-based drug design techniques
Estimation of the three-dimensional pharmacophore of ligands for rat multidrug-resistance-associated protein 2 using ligand-based drug design techniques
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DOI：
10.1007/s01869-005-1869-8
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发表时间：
2005-02-01
影响因子：
3.7
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Hirono, S;Nakagome, L;Sugiyama, Y
目的。多药耐药相关蛋白 2 (Mrp2) 对两亲性有机阴离子表现出广泛的底物特异性。这项研究确定了与大鼠 Mrp2 结合的配体分子的关键功能基团，并确定了它们的相对位置。并使用三维 (3D) 定量结构-活性关系 (3D-QSAR) 分析通过受体作图检查底物特异性。方法。使用构象分析 (CAMDAS) 和分子叠加 (SUPERPOSE) 方法估计配体结合构象，以阐明与 3D 配体结构相关的大鼠 Mrp2 的底物特异性。结果。鉴定了大鼠 Mrp2 配体的两种类型的结合构象。 3D-QSAR 比较分子场分析 (CoMFA) 揭示了一种类型的统计显着模型，其中空间、静电和 log P 对大鼠 Mrp2 结合亲和力的贡献分别为 63.0%、33.4% 和 3.6%（n = 16、q(2) = 0.59、n = 3、r(2) = 0.99 和 s = 0.08).结论。估计了大鼠 Mrp2 配体的 3D 药效团以及大鼠 Mrp2 的配体结合区域。大鼠 Mrp2 的配体识别是通过两个疏水位点和两个正静电位点（主要结合位点）的相互作用实现的。大鼠 Mrp2 的广泛底物特异性可能是由次级（两个静电正性位点和两个静电负性位点）和初级结合位点的组合产生的。
Purpose. Multidrug-resistance-associated protein 2 (Mrp2) shows a broad substrate specificity toward amphiphilic organic anions. This study identified key functional groups of ligand molecules for binding to rat Mrp2, determined their relative locations. and examined substrate specificity through receptor mapping using three-dimensional (3D) quantitative structure-activity relationship (3D-QSAR) analysis.Methods. Ligand-binding conformations were estimated using conformational analysis (CAMDAS) and molecular superposition (SUPERPOSE) methods to clarify the substrate specificity of rat Mrp2 in relation to 3D ligand structures.Results. Two types of binding conformations of ligands for rat Mrp2 were identified. 3D-QSAR comparative molecular-field analysis (CoMFA) revealed a statistically significant model for one type, in which the steric, electrostatic, and log P contributions to the binding affinity for rat Mrp2 were 63.0%, 33.4%, and 3.6%, respectively (n = 16, q(2) = 0.59, n = 3, r(2) = 0.99, and s = 0.08).Conclusions. The 3D pharmacophore of ligands for rat Mrp2, and the ligand-binding region of rat Mrp2, were estimated. Ligand recognition of rat Mrp2 is achieved through interactions in two hydrophobic and two electrostatically positive sites (primary binding sites). The broad substrate specificity of rat Mrp2 might result from the combination of secondary (two electrostatically positive and two electrostatically negative sites) and primary binding sites.