Marriott D P, Dougall I G, Meghani P, Liu Y J, Flower D R
Department of Physical and Metabolic Sciences, Astra Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
J Med Chem. 1999 Aug 26;42(17):3210-6. doi: 10.1021/jm980409n.
By using a pharmacophore model, a geometrical representation of the features necessary for molecules to show a particular biological activity, it is possible to search databases containing the 3D structures of molecules and identify novel compounds which may possess this activity. We describe our experiences of establishing a working 3D database system and its use in rational drug design. By using muscarinic M(3) receptor antagonists as an example, we show that it is possible to identify potent novel lead compounds using this approach. Pharmacophore generation based on the structures of known M(3) receptor antagonists, 3D database searching, and medium-throughput screening were used to identify candidate compounds. Three compounds were chosen to define the pharmacophore: a lung-selective M(3) antagonist patented by Pfizer and two Astra compounds which show affinity at the M(3) receptor. From these, a pharmacophore model was generated, using the program DISCO, and this was used subsequently to search a UNITY 3D database of proprietary compounds; 172 compounds were found to fit the pharmacophore. These compounds were then screened, and 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenylethanone (pA(2) 6.67) was identified as the best hit, with N-[2-(piperidin-1-ylmethyl)cycohexyl]-2-propoxybenz amide (pA(2) 4. 83) and phenylcarbamic acid 2-(morpholin-4-ylmethyl)cyclohexyl ester (pA(2) 5.54) demonstrating lower activity. As well as its potency, 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenylethanone is a simple structure with limited similarity to existing M(3) receptor antagonists.
通过使用药效团模型（一种分子展现特定生物活性所需特征的几何表示），可以搜索包含分子三维结构的数据库，并识别可能具有该活性的新型化合物。我们描述了建立一个实用的三维数据库系统的经验及其在合理药物设计中的应用。以毒蕈碱M(3)受体拮抗剂为例，我们表明使用这种方法可以识别出有效的新型先导化合物。基于已知M(3)受体拮抗剂的结构生成药效团、进行三维数据库搜索以及中通量筛选，以识别候选化合物。选择了三种化合物来定义药效团：一种由辉瑞公司申请专利的肺选择性M(3)拮抗剂，以及两种在M(3)受体上显示亲和力的阿斯利康化合物。由此，使用DISCO程序生成了一个药效团模型，随后用它来搜索一个包含专利化合物的UNITY三维数据库；发现有172种化合物符合该药效团。然后对这些化合物进行筛选，1-[2-(2-(二乙氨基)乙氧基)苯基]-2-苯乙酮（pA(2) 6.67）被确定为最佳命中物，N-[2-(哌啶-1-基甲基)环己基]-2-丙氧基苯甲酰胺（pA(2) 4.83）和苯基氨基甲酸2-(吗啉-4-基甲基)环己酯（pA(2) 5.54）的活性较低。除了其效力外，1-[2-(2-(二乙氨基)乙氧基)苯基]-2-苯乙酮结构简单，与现有的M(3)受体拮抗剂相似度有限。
