显著的遗传多态性导致CYP2D6酶活性广泛性改变，因此产生的药代动力学变化是引起底物药物疗效个体差异的重要原因。虽然新变异不断被发现，但对应的功能研究却相对滞后；其结构和活性改变的分子机理仍不清晰。本项目组基于前期研究发现的新型CYP2D6变异体，通过酶动力学研究与基于计算机的分子对接，发现不同变异体对β受体阻断剂的酶动力学特征呈现差异，但底物与野生型蛋白的结合域相似且与血红素垂直。因此我们假设：CYP2D6酶活性口袋中与血红素垂直区域的构象改变是产生活性差别的重要原因。同时我们寻找到了携带新型变异体的受试者并明确了对应的基因型。本项目拟利用生物信息分析技术研究底物结构、变异位点与酶活性的相关性；通过结构生物学技术在分子水平阐明酶活性改变的机理；基于PK-PD模型明确新基因型的临床代谢表型。建立“基因-分子结构-临床表型”关系，为临床精准应用CYP2D6底物药物提供理论依据和数据支持。

The genetic polymorphisms of CYP2D6 lead to extensive change in enzyme activity. It’s the main reason that causing dramatic change in pharmacokinetic profiles and individual differences in the efficacy of substrate drug. Although novel variants of CYP2D6 are constantly being discovered, the corresponding functional studies are relatively lagging. The molecular mechanism underlies structure and activity changes are still unclear. In our previous studies, we discovered some novel CYP2D6 variants. By using enzyme kinetics study, we found that variants exhibit significant differences in enzyme kinetic profiles of β-blockers. However, these β-blockers have the similar binding domain in CYP2D6, which is perpendicular to heme. Therefore, we hypothesized that the conformational change in the vertical region above heme in the activity center of CYP2D6 is the main reason that lead to vary in activity among drugs. Meanwhile, we found the subjects carrying the new variants and identified the corresponding genotypes. This project intends to use bioinformatics technology to study the correlation among substrate structure, mutation site and enzyme activity; to elucidate the molecular mechanism of enzyme activity change at the molecular level through structural biology techniques; to define the clinical metabolic phenotype of new genotypes based on PK-PD model. A "gene-molecular structure-clinical phenotype" relationship would be established to provide theoretical basis and data support for clinically accurate application of CYP2D6 substrate drugs.