尼古丁生物降解产物中烟碱型乙酰胆碱受体α7亚型靶向化合物的虚拟筛选
Virtual screening of the targeted compounds of the nicotinic acetylcholine receptor α 7 subtype in nicotine biodegradation products
云南民族大学学报:自然科学版,2017,26(3):197-201

毕红磊 BHL

摘要


在以微生物降解尼古丁的代谢途径中,已被分离出多种与尼古丁结构类似的中间产物.烟碱型乙酰胆碱受体α7亚型(α7-nAChR)是阿尔茨海默病和多种炎症药物研发的重要靶点,而尼古丁是与其特异性结合的天然配体.计算机虚拟筛选技术是现代新药研发的一种重要方法.采用尼古丁降解产物及其结构相似物与α7-nAChR进行活性位点对接及分子计算,探寻是否可以从尼古丁的降解产物中寻找出新型以α7-nAChR为靶点的小分子治疗药物.选用9个尼古丁代谢的中间产物和与其结构相似的78个化合物为筛选对象.计算结果显示:9个尼古丁代谢中间产物与α7-nAChR的结合能量在-5.7 kcal/mol~-6.7 kcal/mol之间,3个结构相似化合物与α7-nAChR的结合能量约为-8.0 kcal/mol.这些化合物均可以与α7-nAChR的活性区域进行结合,其结合能与其天然配体接近或更好.筛选的结果为此类化合物的下一步的药理学研究提供了参考. A variety of metabolites can be isolated from the microbial metabolic pathway of nicotine. Studies have shown that the nicotinic acetylcholine receptor α 7 subtype (α 7-nAChR) is a crucial therapeutical target for Alzheimers disease and some inflammatory diseases, and nicotine is a natural ligand which can specifically bind it. As an important modern drug discovery, the virtual screening technology is used in the present study to evaluate the α 7-nAChR-binding capacities of nicotine degradation products and their analogues with the expectation to find novel α 7-nAChR targeting small molecule drugs. Nine nicotine metabolites and 78 compounds with similar structures are selected as the screening targets. The binding energies of the 9 nicotine metabolites are from -5.7 kcal/mol to -6.7 kcal/mol, and those of 3 analogues are about -8.0 kcal/mol. These 12 compounds are expected to combine with the active region of α 7-nAChR close to or better than its natural ligand. The results of the present study provide the possibility for the follow-up pharmacological investigations and further developments of these compounds.

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