Bloom(BLM)解旋酶在维护基因组稳定性方面发挥巨大作用，其突变会导致Bloom综合症的发生，并伴随严重的癌症倾向，其分子机理尚不清楚。BLM解旋酶小分子抑制剂的发现能为深入理解其分子机理提供重要信息，但其抑制剂却鲜有报道。申请人在前期对BLM解旋酶生物学活性进行大量研究的基础上，拟基于已有化合物库，采用虚拟筛选与蛋白质热转移技术初筛获得与BLM解旋酶亲和力较高的小分子化合物，并采用基于停流技术的抑制活性筛选发现其新型小分子抑制剂。拟采用多角度综合分析技术，分析小分子抑制剂与BLM解旋酶复合物晶体，结合等温滴定量热法测定的热力学参数与分子模拟相互作用参数，揭示BLM解旋酶的分子机制。该研究有助于深刻理解BLM解旋酶在维持染色体稳定性中的重要作用，探讨Bloom综合症的分子致病机理，并为Bloom综合症的治疗及依赖于BLM增殖的抗肿瘤先导药物或化疗药增敏剂的研发提供实验基础与科学依据。

BLM helicase plays a significant role in maintaining the stability of genome. The genetic mutations in this enzyme will lead to Bloom’s syndrome and accompany with predisposition to various cancers. However, its molecular mechanism is unclear. It will provide valuable information for a deeper and comprehensive understanding on its molecular mechanism to discover small molecular inhibitors of BLM helicase. There are rare reports on it. The applicant puts forward this research project based on fruitful study results on biological activities of BLM helicase as followings: (1) Small molecular compounds with high affinity to BLM helicase can be obtained based on both virtual screening method and protein thermal shift assay. Subsequently, new small molecular inhibitors can be discovered through activity screening based on stopped-flow spectroscopy assay. (2) The molecular mechanism can be elucidate by a comprehensive analysis from multi-angles concerning complex crystal structure of BLM helicase and its inhibitors, thermodynamic parameters from isothermal titration calorimetry and interactive function analysis from molecular docking. The research results are valuable to understand significant role of BLM helicase in maintaining chromosomal stability and to analyze molecular nosogenesis of Bloom disease. Furthermore, this research would also provide experimental and scientific basis for treatment of Bloom disease and development of anti-cancer leading compounds and sensitizers related to proliferation of BLM helicase.