Molecular modeling of σ1 receptor ligands:: a model of binding conformational and electrostatic considerations
Molecular modeling of σ1 receptor ligands:: a model of binding conformational and electrostatic considerations
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DOI：
10.1016/j.jmgm.2003.08.001
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发表时间：
2004-01-01
影响因子：
2.9
通讯作者：
Jung, D
中科院分区：
文献类型：
--
作者：
Gund, TM;Floyd, J;Jung, D
我们对几种 sigma1 特异性配体（包括 PD144418、spipethiane、氟哌啶醇、喷他佐辛等）进行了分子建模研究，以开发用于 sigma1 受体-配体结合的药效团，假设所有化合物在同一受体结合位点相互作用。建模研究研究了配体的构象和静电特性。 活性分子的叠加给出了假设的 5 点 sigma1 药效基团的坐标，如下： R1 (0.85, 7.26, 0.30)； R2（5.47，2.40，-1.51）； R3（-2.57，4.82，-7.10）； N (-0.71, 3.29, -6.40);碳质心（3.16， 4.83，-0.60)，其中R1、R2构建在每个化合物的芳香环上，代表与受体的疏水相互作用； R3表示氮原子与受体之间的氢键。使用额外的分析来描述与电负性基团（例如氧或硫原子）的次级结合位点。这些坐标是 (2.34, 5.08, -4.18)。的 通过拟合其他 sigma1 受体配体验证了模型。该模型可用于搜索构象数据库以寻找其他可能的活性配体。与合理的药物设计技术相结合，该模型可用于设计和合成具有高选择性和效力的新型 sigma1 配体。使用 Sybyl 6.5 进行计算。 (C) 2003 Elsevier Inc. 保留所有权利。
We have performed molecular modeling studies on several (sigma1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5. (C) 2003 Elsevier Inc. All rights reserved.