以酶为靶点的药物设计.ppt

* Medicinal Chemistry * 2.3 The Active Site of Neuraminidase Fig 4. The active site of NA Biochemistry, 2001, 42:718-727 Fig 5. The “airplane” model of NA active site J Med Chem, 2003,44(8):1192-1201 Babu et al demonstrated that what is important for potent NA inhibition is not the absolute position of the central ring but rather the relative positions of the interacting groups. “Using structural information about drug targets or their natural ligands as a basis for the design of effective drugs.” positive charge and hydrogen bonding environment negative charged region small hydrophobic region Large hydrophobic region mixed polarity 2.4 The structure of neuraminidase inhibitors Fig.7 Structure of NA inhibitors (J Zhang and WF Xu, Mini-Review in Medicinal Chemistry,2006(4):429~448) Chapter 4. Drug Design based on Enzyme as Targets 在已知的约500种药物作用靶标中，酶是最重要的一类，约占45%。 未来将有5000~7000种靶标成为药物设计与研究的实用性靶标，其中约3500种是酶靶 Section 1. Basic Knowledge of Enzyme 分类依据 分类 举例 酶在细胞的位置 细胞表面酶（cell surface enzyme）/胞外酶(extracellular enzyme) 羟甲戊二酰辅酶A还原酶(3-hydroxy-3-methylglutaryl coenzyme A reductase，HMG CoA还原酶) 血管紧张素转化酶(angiotensin-converting enzyme，ACE ) 一氧化氮合成酶(nitric oxide synthase, NOS) 乙酰胆碱酯酶(acetylcholinesterase, AcChE) 胞内酶（intracellular enzyme） DNA聚合酶(DNA polymerase) 半胱天冬酶(caspase) 酶催化反应类型 氧化-还原酶(oxidoreductase) 单胺氧化酶(monoamine oxidase，MAO)、细胞色素酶(cytochrome) 水解酶(hydrolase) 淀粉酶(amylase)、蛋白酶(protease) 转移酶(transferase) 法尼基转移酶(farnesyl transferase)、磷酸化酶(phosphorylase) 异构酶(isomerase) 前列腺素异构酶(prostaglandin isomerase) 连接酶(ligase) tRNA连接酶(tRNA ligase) 裂和酶(lyase) 碳酸酐酶(carbonate dehydratase)、醛缩酶(aldolase) I. kinetics of enzyme-catalyzed reactions （一）底物浓度对反应速度的影响 底物浓度对酶促反应速度的影响 米氏方程 ： 在底物浓度很低的条件下υ与[S]呈线性关系，结果υ = [S]Vmax/KM； 当底物浓度接近饱和时，υ与[S]无关并且趋于最大反应速度Vmax II. Interaction of E-I complex 底物或抑制剂与靶酶的亲和力是各种作用力的综合结果(静电作用、范德华力、疏水作用、氢键和阳离子-?键)。 Ki = [E][I]/[E · I] Ki值越小，抑制作用越强。 Activation and Inhibition of Enzyme I. Activation of Ensyme 1. 酶原的激活:这种无活性的酶的前体称作酶原，酶原向酶转化的过程称为酶原的