肿瘤细胞对化疗药物的多药耐药性（MDR）是化疗失败的主要原因，肿瘤的MDR现象产生的途径较多，有其复杂的分子生物学机制，其中研究最多的机制为药物摄入减少或者药物外排增加（主要通过P-gp蛋白介导），目前针对该机制的肿瘤增敏剂已经开发了三代，但临床应用多表现出毒性和副作用。研究发现，天然产物肿瘤增敏剂有可能克服这些毒副反应，前期我们研究发现来源于绞股蓝皂苷元类成分H6（结构见报告正文）具有很好的逆转MDR作用，下一步我们将以H6为先导物，以P-gp蛋白为靶标，利用计算机辅助药物设计的基本原理，设计并制备系列结构衍生物并进行MDR活性评价。同时总结其抗MDR构效关系，指导并期望寻找活性更好、毒性更低和具有优良ADME性质的逆转MDR药物侯选物，为研制创新药物奠定坚实的基础。我们希望通过计算机辅助药物设计进行基于中药中活性成分的新药开发研究这一案例，为中药的现代化开发提供新的研究思路。

Multiple drug resistance (MDR) in cancer cells is characterized in vitro by cross-resistance towards many different anticancer agents that have no common chemical structure, pharmacological target, or metabolic pathway. ‘‘Classical MDR’’ is attributed to the overexpression of plasma membrane P-glycoprotein (P-gp) in resistant cells. Its activity results in a marked reduction in the intracellular concentration of a wide range of substrates including anticancer drugs. Efflux of these drugs out of cells by P-gp is a reason for failure of chemotherapy. P-gp-mediated drug efflux and the associated intracellular accumulation deficit can be circumvented by a wide range of compounds, many of which are common pharmaceuticals in clinical use for conditions other than cancer. .To date, third-generation inhibitors of P-pg have been developed but none are approved for use clinically due to their unwanted side effects. Therefore, the search for more potent chemosensitizers with desirable pharmacology is of paramount clinical importance. Agents derived from plant origin are being increasingly utilized in drug discovery and in drug development programs. Identifying natural compounds capable of circumventing MDR with minimal adverse side effects is an attractive goal..As part of our ongoing research of identifying novel chemosensitizers from medicinal plants, a series of damarane-type gypenoside of Gynostemma pentaphyllum, a perennial climbing herb that grows wildly in Southern China has been identified to circumvent Vincristine resistance in KB/VCR cells, and Sorafenib resistance in HepG2/Sora and 7721/Sora cells. The present study demonstrates that one of the gypenoside, H6 prepared from Gynostemma pentaphyllum exhibited potent and specific reversal of VCR resistance in KB/VCR cells, and Sorafenib resistance in HepG2/Sora and 7721/Sora cells. It is likely that H6 as a lead compound could provide a rational approach for the design of selective anticancer treatment regimens for the treatment of cancer clinically.