Quantitative conformationally sampled pharmacophore for δ opioid ligands:: Reevaluation of hydrophobic moieties essential for biological activity
Quantitative conformationally sampled pharmacophore for δ opioid ligands:: Reevaluation of hydrophobic moieties essential for biological activity
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DOI：
10.1021/jm0612463
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发表时间：
2007-04-19
影响因子：
7.3
通讯作者：
MacKerell, Alexander D., Jr.
中科院分区：
文献类型：
--
作者：
Bernard, Denzil;Coop, Andrew;MacKerell, Alexander D., Jr.
最近的研究表明δ阿片样物质激动剂和拮抗剂的几种治疗应用。为了开发δ阿片样物质的治疗潜力，开发δ阿片样物质受体上配体活性的结构基础是必不可少的。构象采样药效团（CSP）方法（Bernard等人，J. Am. Soc.2003，125，3103-3107），以获得δ阿片样物质配体功效和亲和力的定量模型。通过配体采样的构象空间相对于参比化合物的重叠积分进行定量。CSP模型的迭代细化确定了除传统苯丙氨酸残基以外的疏水基团对DSLET和ICI 174 864中的功效和亲和力很重要。所获得的肽和非肽δ阿片样物质配体的结构多样性集合的模型提供了良好的预测，R-2值> 0.9，并且一组测试化合物的预测功效与实验值一致。
Recent studies have indicated several therapeutic applications for delta opioid agonists and antagonists. To exploit the therapeutic potential of delta opioids developing a structural basis for the activity of ligands at the delta opioid receptor is essential. The conformationally sampled pharmacophore (CSP) method (Bernard et al. J. Am. Chem. Soc. 2003, 125, 3103-3107) is extended here to obtain quantitative models of delta opioid ligand efficacy and affinity. Quantification is performed via overlap integrals of the conformational space sampled by ligands with respect to a reference compound. Iterative refinement of the CSP model identified hydrophobic groups other than the traditional phenylalanine residues as important for efficacy and affinity in DSLET and ICI 174 864. The obtained models for a structurally diverse set of peptidic and nonpeptidic delta opioid ligands offer good predictions with R-2 values > 0.9, and the predicted efficacy for a set of test compounds was consistent with the experimental values.