XRAY CRYSTALLOGRAPHIC STUDIES OF DRUG DESIGN TARGETS

本建议书描述了两个涉及结构的项目 确定作为药物设计目标的蛋白质。 之一 微粒体甘油三酯转移蛋白（MTP）是一种 参与脂质和磷脂在 肝脏和肠的膜。 建议抑制剂 MTP会阻止肝脏和肠道对胆固醇的吸收 并提供显著更有效的降低胆固醇 治疗 另一个项目涉及_-葡萄糖醛酸苷酶， _-葡糖醛酸来自糖胺聚糖，是一种必需酶 这些细胞外基质成分的正常周转。 _-葡萄糖醛酸酶和其他溶酶体酶被释放到 炎症性关节疾病如类风湿性关节炎 关节炎的症状。 正在努力 使这两种酶在抑制剂存在下共结晶 作为互动药物设计项目的一部分。

This proposal describes two projects involving structure determinations of proteins that are drug design targets. One of these, Microsomal Triglyceride Transfer Protein (MTP), is a protein involved in the transport of lipids and phospholipids between membranes in the liver and intestine. It is proposed that inhibitors of MTP will block the uptake of cholesterol in the liver and intestine and provide dramatically more effective cholesterol lowering therapies. The other project involves _-glucuronidase, which cleaves _-glucuronic acid from glycosaminoglycans and is an essential enzyme for the normal turnover of these extracellular matrix components. _-glucuronidase and other lysosomal enzymes are released into the synovial fluid in inflammatory joint diseases such as rheumatoid arthritis where they contribute to the symptoms. Efforts are underway to cocrystallize both of these enzymes in the presence of inhibitors as part of an interactive drug design project.