乙酰胆碱M3受体拮抗剂的从头设计  

De Novo design of acetylcholine M3 receptor antagonist

作　　者：康从民[1] 刘冬青[1] 李宁[1,2] 程家高[3] 吕英涛[1] 

机构地区：[1]青岛科技大学化工学院,山东青岛266042 [2]山东药品食品职业学院,山东威海264210 [3]华东理工大学药学院,上海上海200237

出　　处：《计算机与应用化学》2015年第3期285-290,共6页Computers and Applied Chemistry

基　　金：国家自然科学基金资助项目(21072111,21172070,21272131);山东省自然科学基金资助项目(ZR2011BM015)

摘　　要：M3受体是人体内分布广泛的一种重要的毒蕈碱乙酰胆碱受体亚型,与膀胱过度活动症、心律失常、呼吸道及支气管疾病密切相关.设计与合成M3受体拮抗剂对于开发治疗相关疾病的药物具有重要理论意义和应用价值。本文采用同源模建方法,构建了人M3受体蛋白的三维结构,基于M3受体拮抗剂的结构构建了其药效团模型,其中较理想的模型含有6个药效团特征元素。利用药效团模型进行了虚拟筛选,虚拟筛选的数据库是本实验室构建的虚拟化合物库,发现了10个新型的对M3受体有拮抗作用的化合物。最后对这10个化合物进行了分子对接,根据对接结果,发现3个化合物对接能量及结合方式比较合理,为M3受体拮抗剂的合成研究及活性测定奠定了基础。M3 receptor is one of the most important muscarinic acetylcholine sub-type receptors, and is widely distributed in the human body. Selective M3 receptor antagonists can competitively bind to M3 receptors. It is used to treat Overactive Bladder, Chronic Obstructive Pulmonary Disease, Irritable Bowel Syndrome and other diseases. We constructed a three-dimensional model of M3 muscarinic acetylcholine receptor protein by homology modeling, and assessed the reliability of the model using MODELLER software. Then, 7 compounds reported M3 receptor inhibitors were chosen to construct several pharmacophore models with the help of the SYBYL software. The best phannacophore model consists of six features including three hydrogen-bonding donors, one hydrogen-bonding acceptors, one hydrophobic core, and one aromatic ring center. Then, we use this pharmacophore model to a UNITY database searching, discovered 10 new compounds. Finally, through the molecular docking three molecules which have lower binding energy were got. This study will contribute to the design and synthesis of new-type M3 receptor antagonists.

关 键 词：M3受体 同源模建 药效团模型 虚拟筛选 分子对接 

分 类 号：R914.2[医药卫生—药物化学] O64[医药卫生—药学]