药物分子设计的策略_苗头和先导物的品质决定新药的成败.docVIP

药物分子设计的策略:苗头和先导物的品质决定新药的成败 郭宗儒 3 (中国医学科学院药物研究所, 北京100050 摘要:苗头化合物2先导物2候, 节, 将创制过程分成研究和开发两个阶段, , 所以决定了临床前和临床研究的命运。, 苗头化合物演化, , 是在药效、药代、、确定先导物、先导物优化; ; 先导物; 候选药物; 配体效率; 优化 :　　　文献标识码:A 　　　文章编号:0513-4870(2008 09-0898-07 收稿日期:2008204203. 3 通讯作者　Tel /Fax:86-10 E 2mail:zrguo@i m m. ac . cn Strategy of molecul ar drug desi gn:hits, leads and drug candi dates G UO Zong 2ru 3 (Institute of M ateria M edica, Chinese A cade m y of M edical Sciences, B eijing 100050, China Abstract:H its, leads and drug candidates constitute three m illst ones in the course of drug discovery and devel opment . The definiti on of drug candidates is a critical point in the value chain of drug innovati on, which not only differentiates the research and devel opment stages, but more i m portantly, deter m ines the pers pective and destiny of the p re 2clinical and clinical studies . A ll outcomes fr om the devel opment stage are actually attributed t o the che m ical structure of candidates . The quality of candidates, however, is restricted by the drug 2likeness of lead compounds, which in turn is decided by the characteristics of hits . The hit 2t o 2lead is t o p r ovide a p r om ising and druggable structure f or further devel opment, whereas the op ti m izati on of lead compounds is a p r ocess t o transfor m an active compound int o a drug, which in essence is molecular mani pulati on in multi 2di m ensi onal s pace related t o phar macodyna m ic, phar macokinetic, physico 2che m ical, and safety p r operties . This revie w discusses the strategic p rinci p les in hit discovery, lead identificati on and op ti m izati on, as well as drug candidate definiti on with p ractical exa mp les . Key words:molecular drug design; hit; lead; drug candidate; ligand efficiency; op ti m izati on 1　新药创制的过程和知识价值链:确定候选药物是 药物研发价值链的中心环节 新药的创制过程是将非药的活性化合物向成药转化, 以臻于满足安全、有效、稳定和质量可控的要求。转化过程由许多环节组成, 包括生物学方面的活性评价模型和评价方法; 在化学上是发现苗头化 合物(hit 和(或 先导化合物(lead , 通过优化结 构, 确定一批有成药前景的物质, 即候选药物(drug candidate ; 然后按照药政法