甲状旁腺素受体激动剂3D药效团模型的构建与应用  

3D Pharmacophore Model of Parathyroid Hormone (PTH) Agonists

作　　者：朱冬吉[1] 林克江[1] 尤启冬[1] 

机构地区：[1]中国药科大学药物化学教研室,江苏南京210009

出　　处：《药物生物技术》2012年第5期437-442,共6页Pharmaceutical Biotechnology

摘　　要：甲状旁腺素能增加人体骨密度和骨强度,是治疗骨质疏松症最有效的多肽类药物之一,但至今缺乏具有相应功能的小分子药物。根据计算机辅助药物设计原理,采用Discovery Studio 2.5软件包,以14个甲状旁腺素(PTH)受体激动剂及其突变类似物为训练集,利用活性构象限制的方法,采用HypoGen算法构建出具有活性预测功能的3D药效团模型。其中最好的药效团模型含有1个阳离子基团(PI),3个疏水中心(H)和1个氢键供体(HBD)。同时应用该模型成功预测出16个测试集分子的活性,经交叉验证表明该模型达到95%的置信水平,具有良好的活性预测能力。该药效团可以用于后续抗骨质疏松症小分子药物的筛选,指导相应的药物优化,同时所采用的限制构象的药效团生产方法为基于多肽的药物设计提供了一个新的思路。Parathyroid hormone（PTH） increases bone mineral density and bone strength in humans and indeed is now considered as one of the most effective polypeptide drugs for osteoporosis. However none of small molecular drugs which have similar functions has been approved for use against osteoporosis. In this article the principle of Computer Aided Drug Design （CADD） was used. A pharmacophore model was developed in Discovery Studio 2.5 （ DS 2.5） software based on 14 reported available polypeptide parathyroid hormone-1 receptor （PTH1R） agonists. The best pharmacophore model consists of three features namely one positive ionizable point （PI） ,three hydrophobic points （H） and one hydrogen bond donor （HBD）. The application of the model shows the great success in predicting the activities of 16 known PTH1R agonists. The model has a cross validation of 95% confidence level, suggesting that highly predictive pharmacophore model was successfully obtained. This pharmacophore model can be used for follow-up screening of potential drugs of anti-osteoporosis. It can also be regarded as an instruction for drug structral optimization. The method of comformational restriction used in this article for pharmacophore generation provides a new idea for polypeptide based drug design.

关 键 词：骨质疏松症 甲状旁腺素(PTH) 计算机辅助药物设计(CADD) 药效团 HypoGen算法 激动剂 

分 类 号：TQ467.4[化学工程—制药化工] Q514.3[生物学—生物化学]