基于昆虫气味结合蛋白的新型酰基哌啶类化合物的构效关系

Structure Activity Relationship Studies on Novel Acylpiperidine Compounds Based on Insect OBP1

利用Sybyl7．3软件对29个具有驱避活性的新型酰基哌啶类化合物与气味结合蛋白AgamOBPl的结合模式进行研究，发现二者之间的结合以疏水作用和水桥作用为主．其中酰基哌啶类化合物末端的疏水片段可与AgamOBPl结合腔内狭长的疏水通道产生相互作用．同时，其关键药效基团——酰基氧可通过HOHl53与AgamOBPl中的关键残基Twll4和Gly92或Cys95形成多重氢键作用．利用比较分子力场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）构建了新型酰基哌啶类化合物的三维定量构效关系（3D—QSAR）模型，其交叉验证系数r：。分别为0．650和0．587．研究表明，在CoMSIA模型中，疏水场、静电场和立体场组合所得的三维构效关系模型最佳，其中尤以疏水场对这类酰基哌啶类化合物的驱避活性最为重要．基于AgamOBPl靶标结合口袋特征和酰基哌啶类化合物的3D—QSAR模型得出具有驱避活性的酰基哌啶类化合物的构效关系如下：在酰基C上引入一定碳链长度的疏水基团可使化合物表现出驱避活性，其中又以含9～10个C的化合物的驱避活性最佳，这与AgamOBPl结合口袋的疏水性质密不可分；当酰基端碳链长度一定时，在哌啶环上不宜引入立体效应过大的取代基，这是由AgamOBPl结合口袋的大小决定的；与哌啶N相连的酰基作为氢键受体基团，对于化合物识别与结合AgamOBPl蛋白至关重要．

The binding mode between 29 novel acylpiperidine compounds and odorant binding protein AgamOBP1 were studied with Sybyl7.3 software. The results show that the hydrophobic effect and the water- bridge interaction both mainly contribute to their binding affinity. Some terminated hydrophobic groups of these aeylpiperidine compounds are indicated to be embed a hydrophobic, long and narrow tunnel in the binding pocket of AgamOBP1. Their acyl O forms multiple hydrogen bonds with some key residues Trp114 and Gly92 or Cys95 of AgamOBP1 via a water-bridge interaction with HOH153. The comparative molecular field analysis （CoMFA） and comparative molecular similarity indices analysis（CoMSIA） were used to build the 3D-quanti- tative structure-activity relationship （QSAR） models of acylpiperidine compounds. Cross-validation coefficients （ r2cv ） of the obtained CoMFA and CoMSIA models are 0. 650 and 0. 587, respectively. In the best CoMSIA model, the hydrophobic, electrostatic and sterie field effects are found to be important factors for the repellent activities of these acylpiperidine compounds, especially the hydrophobic effect. The structure-activity relation- ship of acylpiperidine compounds is revealed based on the binding pocket feature of AgamOBP1 and their 3D-QSAR models. These acylpiperidine compounds with a 9 or 10 carbon chain are indicated to be the best one in the repellent ability when the substituent group in their piperidine ring is identical in the size and posi- tion. The introduction of a bulky substituent group in the piperidine ring is shown to be unfavorable to the re- pellent activities of these acylpiperidine compounds with the same long hydrophobic carbon chain because of the size limitation of the AgamOBP1 binding pocket. The aeyl group of these acylpiperidine compounds as a hydrogen donor group is proposed to be necessary for recognizing and binding to AgamOBP1. These studies will provide a theoretical foundation for the bio-rational design of novel aeylpiperidine repellent molecules.