Quantitative conformationally sampled pharmacophore for δ opioid ligands:: Reevaluation of hydrophobic moieties essential for biological activity

被引:27
作者
Bernard, Denzil [1 ]
Coop, Andrew [1 ]
MacKerell, Alexander D., Jr. [1 ]
机构
[1] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA
关键词
D O I
10.1021/jm0612463
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1799 / 1809
页数:11
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