药物分子设计的策略-药学学报.PDF

药学学报 Acta Pharmaceutica Sinica 2010, 45 (5) : 539547 ·539 · ·综述· 药物分子设计的策略: 理活性与成药性 郭宗儒* ( 中国医学科学院药物研究所, 北京 100050) 摘要: 化合物的内在活性和成药性是创新药物的两个基本要素, 活性是药物的基础和核心, 成药性是辅佐 活性发挥 效的必要条件, 两者互为依存。 物在体内的 剂相、 代动力相和药效相可概括为活性和成药性 的展示过程。成 性是 物除活性外的其他所有性质, 包括物理化学性质、生物化学性质、 代动力学性质和 毒副作用, 这是在不同层次上表征药物的性质和行为, 但又相互关联与制约。活性与成药性由化学结构所决定, 体现在微观结构与宏观性质的结合上, 寓于分子的结构之中。先导物的优化是对活性、物化、生化、 代和安 全性等性质的多维空间的分子操作, 因而具有丰富的 物化学内涵。 关键词: 分子设计; 内在活性; 成药性; 先导物优化 中图分类号: R916 文献标识码:A 文章编号: 05 13-4870 (2010) 05-0539-09 Strategy of molecular drug design: activity and druggability * GUO Zong-ru (Institute of Materia Medica, Chinese Academy of M edical Sciences, Beij ing 100050, China) Abstract: Intrinsic activity and druggability represent two essences of innovative drugs. Activity is the fundamental and core virtue of a drug, whereas druggability is essential to translate activity to therapeutic usefulness. Activity and druggability are interconnected natures residing in molecular structure. The pharma- ceutical, pharmacokinetic and pharmacodynamic phases in vivo can be conceived as an overall exhibition of activity and druggability. Druggability actually involves all properties, except for intrinsic activity, of a drug. It embraces physico-chemical, bio-chemical, pharmacokinetic and toxicological characteristics, which are inter- twined properties determining the attributes and behaviors of a drug in di