高通量药物筛选与创新药物研究与讨论讲解材料课件.ppt

高通量药物筛选与创新药物研究;内容;化合物资源;分子生物学 细胞生物学 基因组学 蛋白组学;高通量筛选（HTS）;The Evolution of HTS;高通量筛选;;要素一：高通量筛选模型建立;选择高通量筛选的靶点;Current Drug Targets;靶点确证;;模型设计;体外生化检测;显色反应(Photometry);显色反应方法检测MetAP活性;显色反应方法检测MetAP活性;荧光强度(Fluorescence Intensity);Fluorogenic Peptide Substrate;荧光偏振(Fluorescence Polarization);FP;尺寸变化;IMAP;Protein-DNA Binding FP HTS;Ser/Th Kinase Competitive FP Assay;荧光共振能转移(FRET);Fluorescence Resonance Energy Transfer (FRET);荧光共振能转移;Fluorogenic (Quenched) Substrate;FRET;时间分辨荧光共振能传递（Time Resolved FRET）;LANCE Assay for Kinase;LANCE Assay for Transferase and Nuclear receptor;LANCE Assay for Protease and Helicase;AlphaScreen;AlphaScreen for PIP3;AlphaScreen for cAMP;BRET;闪烁亲近检测法(Scintillation Proximity Assay, SPA);FlashPlate - SPA without Beads;常用的蛋白水解酶检测方法;常用的蛋白水解酶检测方法;常用的激酶检测方法 ;常用的磷酸酯酶检测方法;以酶为靶点;细胞水平检测;荧光成像检测(FLIPR);FLIPR functional screening assay;报告基因;Reporter Gene;Reporter Gene;Quantum dots ;High Content Screening;High Content Screening;Live cell assays to detect translocation of signaling proteins: primary screening lead profiling Pathway screening for functional effect, rather than specific mode of action (e.g.: in vitro binding, catalytic activity). Modulation of protein translocation is an alternative to inhibition of catalytic activity: protein translocation modulators.;Protein Translocation is Essential for Intracellular Signaling;;GFP Fusion Proteins for Detecting Translocations;Membrane to Cytoplasm Translocation;Cytoplasm to Nucleus Translocation;Vesicle to Plasma Membrane Translocation;Cytoplasm to Membrane Translocation;要素二：化合物样品库制备;Lipinski规则;Properties of an “Average” Drug;Undesirable Compounds;筛选样品来源;传统化学合成和分离;组合化学;特点： 化合物数量大，相对结构多样性 易于设计、合成---100,000 compounds (and more!) in a year with a few chemists and automation SAR的产生 Drug-like？ ;发掘天然产物资源;天然化合物库（Nature Product Pool）;天然产物对新药发现和开发的重要性;为什么自然界能产生对人体疾病有效的物质？;为什么20世纪后半叶对从天然产物寻找新药失去了兴趣？;天然产物研究的复活;根据新药的研发过程设计有效的天然产物研究方法;天然产物或其类似物作为药品实例;洛伐他汀 (Lovastatin)(HMG-CoA抑制剂）;环孢菌素A（Cyclosporine A）;紫杉醇;喜树碱及其衍生物;吗