基于芳香乙酰胺脱乙酰基酶(AADAC)的创新药物代谢机制研究

Esterases contribute to the hydrolysis of drugs including ester, amide, and thioester bonds. The contribution of carboxylesterase (CES) 1 and 2 in the hydrolysis of drugs have been extensively investigated, however, the involvement of arylacetamide deacetylase (AADAC) in drug hydrolysis received little attention. Certain Substrates of AADAC overlap with those of CES2 and the differences on the substrate specificity of AADAC and CES2 still remains to be investigated. Hydrolysis metabolites of AADAC are often associated with drug efficacy or toxicity. According to the common characteristics of AADAC substrates, we hypothesized that AADAC is involved in the hydrolysis of drugs with one side of the ester or amide bonds linked to the ring structures and influence the drug efficacy or the side effect. We will choose 3 new drugs, vicagrel, ainuosaite, and allisartan to identify the involved esterases and investigated the role of AADAC in the hydrolysis of new drugs. The inhibitory effects of new drugs and the corresponding metabolites on AADAC will also be evaluated and prediction of AADAC-mediated drug-drug interaction will be performed using the PBPK modeling. We will further explore the interaction between AADAC and drug-related compounds by using the molecular docking, and differentiate the substrate characteristics of AADAC from CES2 to gain a better understanding of AADAC. This study results will guide us to rationally design and modify the structures of compounds, and support the development of new drugs.

酯酶参与含酯键、酰胺键或硫酯键药物的水解代谢，其中羧酸酯酶1(CES1)和2(CES2)的作用已得到广泛研究，而芳香乙酰胺脱乙酰基酶(AADAC)在药物酯水解中的研究较少。AADAC与CES2具有底物重叠，但是其底物谱差异尚不清楚。AADAC水解产物多与药物毒性或药效相关，申请者通过总结AADAC底物结构特征提出假说：AADAC参与酯键或酰胺键一端与环状结构连接的药物水解过程，影响药物药效或毒副作用。本项目拟以酯类创新药物维卡格雷、艾诺赛特和阿利沙坦酯为例，鉴定参与其代谢的酯酶，揭示AADAC在其体内处置的作用；考察药物及其水解产物对AADAC的抑制作用，预测基于AADAC的药物药物相互作用；采用计算机分子对接模型，探索AADAC与药物及其结构类似物之间的相互作用，细化AADAC与CES2的底物谱差异，加深对AADAC的认识。本研究结果将有助于指导药物分子设计与结构改造，支持创新药物研发。

羧酸酯酶1(CES1)和羧酸酯酶2(CES2)的在药物酯水解中的作用已得到广泛研究，而芳香乙酰胺脱乙酰基酶(AADAC)在药物酯水解中的研究较少。本项目以酯类创新药物维卡格雷、艾诺赛特和阿利沙坦酯为例，鉴定参与其代谢的酯酶，揭示AADAC在其体内处置的作用。AADAC和CES2参与肠中维卡格雷的酯水解，且两者作用相当，对于维卡格雷生成活性代谢物H4发挥药理活性具有重要作用。艾诺赛特在肝脏中被AADAC水解，且水解产物对于AADAC有抑制作用，静态模型提示可能会有DDI风险。AADAC在阿利沙坦酯水解实验中作用有限，阿利沙坦酯在肠中主要经CES2水解生成活性代谢物Exp3174，后者渗透性差且为外排转运体P-gp、BCRP和MRP2的底物，导致其系统暴露量低，揭示了其临床口服生物利用度低的原因。本研究结果也提示，在药物发现和开发中，可以根据酯酶及其底物之间的关系，来实现组织靶向、高/低系统暴露量，从而增加药效或减少毒副作用的目的。本基金研究内容已发表4篇相关SCI论文和1篇中文综述，促进了我国酯酶相关研究。