噻虫嗪是烟碱类杀虫剂的代表，具有强内吸活性、作用速度快等特点，实验研究证明其代谢主要是通过CYP2C19酶实现的。目前，该酶参与的噻虫嗪代谢机理、热力学和动力学仍不清楚，因此无法对提高反应活性和选择性进行研究。本项目拟采用量子力学、分子力学和统计力学方法系统研究CYP2C19酶催化噻虫嗪的代谢机制。在研究中，根据酶的晶体结构构建活性中心，由此研究噻虫嗪去甲基化和氧化机理，获得优势反应路径。在此基础上，比较氨基酸残基对代谢速控步骤的影响，明确酶催化活性和本质，剖析代谢的化学原理和催化关键。通过理论计算，设计突变基因催化噻虫嗪的代谢机理，分析突变位点和突变碱基对代谢的影响。本项目的研究可以明确CYP2C19酶催化噻虫嗪的代谢机制，找出影响催化活性的关键因素，对烟碱类杀虫剂的代谢酶进行设计，从而不但为合成高活性代谢酶供理论基础，还可以为CYP2C19催化其他临床药物代谢提供有用信息。

Thiamethoxam is one of nicotinic insecticides. It has the characteristics of strong systemic activity, fast action and so on. Experimental studies have shown that its metabolism is mainly achieved by CYP2C19 enzyme. At present, the metabolic mechanism, thermodynamics and kinetics of thiamethoxam involved the enzyme are still unclear, which makes it impossible to study the improvement of reactivity and selectivity. This project intends to study the metabolic mechanism of thiamethoxam catalyzed by CYP2C19 enzyme through the quantum mechanics, molecular mechanics and statistical mechanics. In the study, the reactive active site is modeled according to the crystal structure of CYP2C19, thereby the demethylation and oxidation mechanism of thiamethoxam are explored and the dominant reaction pathway is obtained. After that, we compare the effects of amino acid residues on the metabolic speed control step, clarify the catalytic activity and nature of the enzyme, and analyze the chemical principles and catalytic key of metabolism. Through theoretical calculations, The metabolic mechanism of thiamethoxam catalyzed by the mutant gene is designed, and the effects of mutation sites and mutant base pairs on the metabolism are analyzed. This project can confirm the metabolic mechanism of thiamethoxam catalyzed by CYP2C19 enzyme, find out the key factors affecting the catalytic activity, and design the metabolic enzymes of nicotinic insecticides. So it is safe to say that this study can not only provide a theoretical basis for the synthesis of highly active metabolic enzymes, but also provide useful information for the metabolism of other clinical drugs catalyzed by CYP2C19.