尿酸盐转运体1(urate-anion transporter 1，URAT1)是经临床验证的抗高尿酸血症药物靶点。新型URAT1抑制剂的研究可为临床急需药物的研发提供理论依据和物质基础。本申请整合应用化学信息学技术，采用基于配体的虚拟筛选技术，通过药效团、定量构效关系、定量结构-选择性关系等多类具有互补特性模型的构建和验证，对具有不同库容量、类药性及易得性的化合物库进行虚拟筛选，同时结合结构优化来发现新型选择性URAT1抑制剂，并进行其生物学功能评价和作用模式研究，为寻找高效低毒的抗高尿酸血症新先导结构以及进一步阐明URAT1的生物学功能奠定基础。多种互补技术的整合应用是项目的一大特色，也是确保获得高活性URAT1抑制剂的重要手段。首轮建模及虚拟筛选已获得了具有显著体内降血尿酸作用的新型URAT1抑制剂，不仅验证了研究策略的合理可行，并且为后续优化设计提供了可靠的研究模式和模板结构。

Urate-anion transporter 1 (URAT1) is a clinically validated target for hyperuricemia. Investigation on the biological functions of novel URAT1 inhibitors will facilitate the discovery of novel drugs urgently needed in clinic. We propose herein an integrated strategy to identify novel URAT1 inhibitors. A ligand-based strategy will be applied and in silico models with complementary natures, such as pharmacophore, QSAR and QSSR models, will be constructed. Chemical databases with different capacity, druglikeness and availability will be virtually screened, and hits identified will be optimized and evaluated in functional assays. Homology modeling and molecular dynamics simulations will be followed to explore the interaction modes of the inhibitors. The results will not only provide new leads for hyperuricemia, but also shed light on the biological function of URAT1. The project is featured by the integration of multiple complementary techniques, which is critical for the acquirement of potent URAT1 inhibitors. As indicated in the preliminary data, potent URAT1 inhibitors with in vivo efficacy have been obtained, which not only validates the feasibility of the research strategy, but also offers new research strategies and chemical templates for further optimization.