现在较为前沿的药物设计原理,望给予需要的人一下一些帮助。

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 drug

molecule. A connective molecule can simply be realized by combining two active molecules or their pharmacophores with a linker; while an integrated molecule comes into an entity either by fusing or by merging the common structural or pharmacophoric features of two active molecules, depending on the extent of the common features. The latter approach facilitates the reduction of molecular size and molecular weight and the optimal overlap between the pharmacodynamic and pharmacokinetic spaces, which will certainly elevate the probability of being a drug.

Key words: strategy of drug design; dual-target drug; new drug research

1 新药研究的两种模式

自从20世纪80年代分子生物学介入到新药研发

收稿日期: 2008-12-12. *

通讯作者 Tel: 86-10-83155752, E-mail: zrguo@imm.ac.cn

领域后, 新药创制模式发生了巨大变化, 在20世纪80年代以前, 研制新药和评价化合物的活性, 主要是以动物模型、离体器官或组织以及细胞的生理学或表型变化为指标, 观察生物体的宏观现象作为新药的评价体系。1980年后, 以研究正常组织与病理状