药物分子设计的策略_双靶标药物设计_郭宗儒.pdf

药学学报 Acta Pharmaceutica Sinica 2009, 44 (3): 209?218 · 209 · ·综述 · 药物分子设计的策略：双靶标药物设计 郭宗儒* (中国医学科学院、北京协和医学院药物研究所, 北京 100050) 摘要: 新药研究可分两种模式：以生理学和表型为基础的研究和以生物靶标为核心的药物研究，这两种模式 相互补充和印证。当今以靶标为切入点的模式占主导地位，研发出不少新药。许多疾病如肿瘤、代谢性和中枢 神经系统疾病的药物治疗非单一靶标可治愈，同时干预与疾病相关的双（多）靶标药物可提高药物的效力，因 而成为创制新药的活跃领域。双靶标药物可以是两个受体的调节剂、两个酶的抑制剂或同时作用于酶和受体或 作用于受体和通道或转运蛋白的双功能性分子等。从药物分子设计的视角，构建双靶标药物分子可将两个活性 分子或其药效团用连接基连接在一起，构成连接型分子；两个活性分子的部分结构或药效团特征相同，可将共 同部分融合或并合，形成融合型或并合型分子，可以控制分子的大小和相对分子质量，使得分子结构的药效空 间与药代动力学空间有较大的重叠，提高成药的几率。 关键词: 药物分子设计策略; 双靶标药物; 新药研究 中图分类号: R916.1 文献标识码: A 文章编号: 0513-4870 (2009) 03-0209-10 Strategy of molecular drug design: dual-target drug design GUO Zong-ru* (Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China) Abstract: Physiology-based and target-based drug discovery constitutes two principal approaches in drug innovation, which are mutually complementary and collaborative. With the target-based approach, a lot of new molecular entities have been marketed as drugs. However, many complicated diseases such as cancer, metabolic disorders, and CNS diseases can not be effectively treated or cured with one medicine acting on a single target. As simultaneous intervention of two (or multiple) targets relevant to a disease has shown improved therapeutic efficacy, the innovation of dual-target drugs has become an active field. Dual-target drug can modulate two receptors, inhibit two enzymes, act on an enzyme and a receptor, or affect an ion channel and a transporter. From viewpoint of molecular design, there are three approaches to construct a dual-target d