从分子水平上阐释雄黄的药效物质及作用机理是解决雄黄安全性和科学性问题的关键和瓶颈。本项目在已有研究的基础上，拟首先应用计算量子化学方法，寻找更多的、稳定的As4S4异构体；然后在计算结果的指导下，对雄黄的药材和饮片进行X-ray衍射分析，来确定雄黄的主要成分；再应用计算量子化学和分子动力学模拟方法，研究雄黄主要成分中的各种As4S4异构体在体内的分解和代谢反应，寻找分解和代谢所产生的中间产物---各形态砷，并研究各形态砷与酪氨酸磷酸酶SHP-2之间的相互作用，推测雄黄抗肿瘤的药效物质和作用机理。最后，在前期计算化学结果的指导下，对雄黄潜在的药效物质进行体外SHP-2酶活抑制剂的筛选实验。从计算和实验两个方面，阐明雄黄抗肿瘤的药效物质和作用机理。本项目的成功实施，不但可以为雄黄抗肿瘤药用的安全性和科学性提供理论依据，还可以为含有重金属矿物药的研究提供一条新思路。

To clarify the effective substance and mechanism at the molecular level is the key and bottleneck of solving the safety and scientific problem of realgar. Firstly, this research will search more and stable As4S4 isomers based on the previous studies by using the method of computational quantum chemistry. Then, under this guidance of the computed results, this research will analyze realgar and its pieces by X-ray diffraction method to determine the main ingredient of it. Next, this research will study the decomposition and metabolic reaction of various As4S4 isomers to obtain the intermediate products - various forms of arsenic, and study the interaction between the various forms of arsenic and tyrosine phosphatase SHP-2 to infer the antitumor effective substance and mechanism of realgar by using the methods of computational quantum chemistry and molecular dynamics simulation; Finally, under this guidance of the preliminary computed results, this research will carry a screening of inhibitors of active SHP-2 enzyme in vitro, and will calrify the antitumor effective substance and mechanism of realgar by combining the computed and experimental results. The successful finishment of this research will not only provide theoretail proofs for solving the safety and scientific problem of realgar, but also provide new ideas for studing other chinese medicine that containing heavy metal.

本项目旨在从分子水平上阐释雄黄的药效物质及其作用机理。本项目首先应用计算量子化学方法寻找并优化了10个As4S4异构体，确定了2个热力学最稳定的异构体分子作为雄黄的主要成分；再应用计算量子化学方法研究了这两个最稳定的As4S4异构体分子的异构化反应和分解反应途径，确定了１个As2S2分子作为As4S4的分解产物。接着，本项目应用计算量子化学和分子动力学模拟方法研究了2个热力学最稳定的As4S4异构体分子分别和盐酸、半胱氨酸、左旋龙脑（冰片成分）以及靛玉红（青黛成分）之间的相互作用，并确定了1个相对稳定的“雄黄－青黛作用的含砷中间体”。根据该计算结果，进行了雄黄配伍青黛的药代动力学实验研究，从计算和实验两个方面解释了雄黄青黛配伍抗肿瘤的药效物质和作用机理，为雄黄青黛配伍治疗癌症提供了理论依据。最后，本项目探索了“雄黄－青黛作用的含砷中间体”与SHP-2之间相互作用。本项目是探索抗癌中药的一个基础性研究。此工作为雄黄抗肿瘤药用的安全性和科学性提供了理论依据，同时也为含有重金属矿物药的研究提供了一条新思路。