维甲类化合物构效关系研究──维甲酸核受体与选择性配体相互作用的分子模拟

STUDIES ON THE STRUCTUREACTIVITY RELATIONSHIP OF RETINOIDS MOLECULAR MODELING OF INTERACTION BETWEEN SELECTIVE RETINOIDS AND NUCLEAR RECEPTORS

目的：研究维甲酸核受体蛋白α，β和γ３种亚型的氨基酸序列差异性，确定可能与抑制剂选择性结合有关的氨基酸残基，揭示维甲酸类药物的毒副作用和与其结合多种受体亚型的关系，设计、开发受体选择性的维甲类分子。方法和结果：基于已解析的γ受体亚型的晶体结构，利用分子图形学和计算化学方法预测了未知的α，β亚型的三维结构；通过３种维甲酸核受体分别与其泛激动剂、选择性激动剂及无结合活性的维甲酸分子之间的分子对接研究，定性解析了抑制剂立体结构上的微小差异导致不同受体产生选择性的本质原因。结论：有选择性受体结合活性的维甲类化合物是进行低毒作用的新型维甲类药物研究和开发的基础。

AIM: All these efforts provide the basis for designing new and selective retinoid drugs. METHODS AND RESULTS: The sequence alignment based upon RAR(retinoic acid nuclear receptors ) crystal structural motifs was performed, and showed that only three amino acid residues of RAR, RAR, RAR in the ligandbinding pocket are at variance. These divergent residues are obvious features to account for the RAR selectivity of certain retinoid. Meanwhile, the ligand binding domains of holoRAR(,) were modeled by site mutagenesis technique. Molecular dynamics relaxing and global minimization were carried out and led to construction of the final complex models. The interaction of RAR(,,) and their specific ligand by docking simulation were investigated, the fine binding patterns have been used to define clearly some important structural characteristics of selective retinoids. CONCLUSION: Receptorspecific retinoids possess improved activity/toxicity profiles compared with the nonselective counterparts. Molecul