药物化学结构和生物活性的课件.ppt

药物化学结构和生物活性的;药物作用的特异性—分子识别;药物作用的特异性;焓(ΔG)作用—静电作用能;静电作用能;静电作用能;静电作用能;焓(ΔG)作用—静电作用能;熵（ΔS)作用—有利的作用;熵（ΔS)作用—不利的作用;药效团概念;药效团表示法;药效团和基本结构;药动团;磷酸基;糖;毒性基团;基团变化对活性的影响;酰基;烷基;卤素;羟基可改变药物的极性、溶解性和氢键作用 巯基由于其稳定性差和亲和性强不用作药物修饰，但可与体内离子结合，含离子的酶抑制剂改造可以应用。巯基丙醇是重金属中毒的解毒剂。 硝基是多种化疗药物的必须基团，引入硝基使得酯溶性增加，偶极矩增加，体内存留时间加长。体内易还原为氨基而发生作用。如9-硝基喜树碱。;药效构象;乙酰胆碱药效构象的证明;三环类抗精神病药物的拓扑结构分析;多巴胺与受体结合的优势构象;二氢吡啶拮抗剂的构象;连苯双酯的药效构象;DNA 潜入剂或干扰剂;DNA 潜入剂或干扰剂;Design and Synthesis of Farnesyltransferase Inhibitors;Cancer Cells and Chemotherapy;Why Molecular Target?;Complicated molecular targets;Function of Ras Proteins;Function of Farnesyltransferase (FTase);Function of Farnesyltransferase;Function of Farnesyltransferase; Crystallgraphic structure of the complex of CAAX and FPP ;Found Inhibitors: CAAX Mimics;IC50=350 nM; Bisubstrate Mimics;Compounds in Clinical Trials ;CAAX mimetics;Why Bezodiazepine as Scaffold?;Privilege Structure is a single molecular framework able to provide ligands for diverse receptors. Selective modification of “privilege structure” known to have provided ligands for diverse receptors in the past.;Bezodiazepine FTase inhibitors;Pharmacophore Comparison of Designed CAAX Mimetics with CAAX;Crystal Analysis ; Comparison of Pharmacophores Between T14 and CAAX;Lead compound T29;Determination of thio compound structure by Crystal analysis ; Bisubstrate Analogues;S-alkyl Thiobenzoate Compounds;Pharmacophore Comparison of Designed Bisubstrate Analogue with CAAX and FPP; ;SYNTHETIC COMPOUNDS;Biological Evaluation;Prospect of FTase target;第五章、定量构效关系和计算机辅助药物设计;Rational Design Advantage;Large-scale determination of protein structures is reversing the drug discovery process by starting with the protein structure and using it to identify and design new ligands. It is the integration of structure-based methods, virtual screening, and combinatorial chemistry that will provide the basis for more efficient drug design in the future, significantly reducing the time of the des