药物分子设计的策略_分子的宏观性质与微观结构的统一
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Key words: molecular drug design; macroscop ic p roperty; m icroscop ic structure; pharmacokinetics; pharmacodynam ics
1 药物作用是由分 子的宏 观性 质与微 观 结构 所决 定
成功的药物应兼有四种属性 :安全性 ,有效性 , 稳定性 (化学和代谢的稳定性 )和可控性 。这些属 性是由药物化学结构所决定 ,寓于分子的结构之中 。
关键词 : 药物分子设计 ; 宏观性质 ; 微观结构 ; 药代动力学 ; 药效学 中图分类号 : R916 文献标识码 : A 文章编号 : 0513 - 4870 (2008) 03 - 0227 - 07
Stra tegy of molecular design of drugs: the un if ica tion of macro2properties and m icro2structures of a molecule
·述 评 ·
药学学报 Acta Pharmaceutica Sinica 2008, 43 (3) : 227 - 233
·22ຫໍສະໝຸດ Baidu·
药物分子设计的策略 : 分子的宏观性质与微观结构的统一
郭宗儒 3
(中国医学科学院 药物研究所 , 北京 100050)
摘要 : 药物与机体的相互作用 ,包含机体对药物的处置和药物对机体的作用 。机体对药物的处置 ,所进行的物 理和化学 、时间和空间的处置 ,遵循一般的规律 ,具有共性特征 ,即分子的整体和宏观性质影响药代动力学行为 。药 物对机体的作用 ,是药物分子与靶标蛋白的物理或化学结合 ,引发药理 (或毒理 )作用 ,起因于药物的特异性作用 ,是 药物分子的个性表现 ,受制于药物分子中特定的原子或基团与靶标分子在三维空间的结合 ,这种微观结构就是药效 团 。药物分子可视作宏观性质与微观结构的集合 ,统一在分子的整体结构之中 ,宏观性质决定药代和物化性质 ,微 观结构决定药理作用 。认识宏观与微观同药代与药效的内在相互关系 ,可以深化对药物作用的认识 ,指导药物分子 设计 。决定分子宏观性质的因素是相对分子质量 、水溶性 、电荷 、脂溶性 (分配性 )和极性表面积等 ,通常是由分子骨 架和整体分子所决定 ,无特异性的结构要求 ;决定活性的微观结构因素有氢键给体 、氢键接受体 、正电中心 、负电中 心 、疏水中心和芳环中心 。不同的生物活性取决于这些不同特征的组合及其空间排布 。分子的宏观性质 ,包含了微 观结构中原子和基团的贡献 ;在改变分子的结构以调整宏观性质时 ,往往影响微观结构的空间位置 。药物分子设计 的技巧是整合这两个因素成最佳配置 ,在早期研究阶段 ,应兼顾宏观性质与微观结构 ,使药效强度和选择性 、药代动 力学和药物的物理化学性质达到最佳的匹配 ,为此 ,要求表征药代的空间与药效学的选择性空间有结构交盖 。
·228·
药学学报 Acta Pharmaceutica Sinica 2008, 43 (3) : 227 - 233
p resum ed as an assembly of m acroscop ic p roperty and m icroscop ic structure, w ith the macroscop ic p roperties determ ining the absorp tion, distribution, metabolism and elim ination of drugs and the m icroscop ic structure coining pharm acological action. The know ledge of the internal relationship between macroscopy /m icroscopy and PK / PD conduces to comp rehension of drug action and guides molecular drug design, because this concep tion facilitates the identification of structural features necessary for biological response, and the determ ination of factors modulating the physico2chem ical and pharmacokinetic p roperties. The factors determ ining macro2p roperties include molecular weight, solubility, charge, lipophilicity (partition) , and polar surface area, etc. , which are destined by molecular scaffolds and /or side chain ( s) apart from pharm acophore. The features of m icro2structures contributing to specific activity contain hydrogen bonding donor and accep tor, positive and negative charge centers, hydrophobic centers and centers of aromatic rings. D ifferent combinations and spacial arrangem ents of these features determ ine the distinct activity p resented. The macro2p roperty and m icro2structure are integrated into a single molecule, and are inseparable. The macro2p roperty reflects overall contribution of atom s and group s in the m icro2structure. On the other hand, structural changes aimed to adjust m acroscop ic p roperty usually alter the relative position of the m icroscop ic structure. The goal of molecular drug design is to integrate the macroscop ic and m icroscop ic factors in op tim ized manner. In the early stage of molecular design, both macroscop ic p roperty and m icroscop ic structure should be considered to make pharmacodynam ics, pharmacokinetics, and physico2chem ical p roperties in op tim al match. Therefore, it required the existence of structural overlapp ing among accep table pharmacokinetics, visible develop ing potential and specific pharmacodynam ics. The larger the scope of overlapp ing, the higher the possibility to be a drug.
药物作为外源性物质 ,被机体视作异物 ,机体为 了保护自己免受外来物质的侵害 ,要对其进行物理 的和化学的处置 ,并在长期进化中 ,面对结构多样性 的外来物质 ,形成了具有共性的处置方式 ,遵循一般 的原则 。这种共性行为 ,表现在吸收 、分布 、体内的 生物转化 、排泄途径 、与血浆蛋白的结合 、组织贮集 等 。研究这些过程与时间的关系 ,就是药代动力学 。 机体对药物的处置 ,通常从整体的结构及其性质出 发 ,在宏观性质上作时间与空间 、物理与化学的处 置 ,一般而言 ,不拘泥分子的细微结构 。
收稿日期 : 2007211209. 3 通讯作者 Tel / Fax: 86210283155752, E2mail: zrguo@ imm. ac. cn
© 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net
GUO Zong2ru3
( Institu te of M a teria M ed ica, Ch inese A cadem y of M ed ica l S ciences, B eijing 100050, Ch ina)
Abstract: The interaction of a drug w ith the organism involves both the disposition of a drug by the organism and the action of a drug on the organism. The disposition of various exogenous substances, including drugs, comp lies w ith general rules. The underlying physical and chem ical changes to different drugs in view of tim e and space, i. e. pharmacokinetics, share common characteristics, that is the tout ensemble of a molecule and its macroscop ic p roperties convey direct effect on the pharm acokinetic behavior as the tendency and consequence of biological evolution. The action of a drug on the organism , on the other hand, imp licates the physico2chem ical binding of a drug molecule to the target p rotein, which induces pharm acological and toxicological effects. The biological reactions, no m atter beneficial or adverse, are all specific and individual m anifestation of the drug molecule and determ ined by the interactive binding between definitive atom s or group s of the drug molecule and the macromolecular target in three2dimension. Such critical atom s, group s, or fragments responsible for the interaction reflect the m icroscop ic structures of drug molecules and are called pharmacophore. In this context, a drug molecule is
1 药物作用是由分 子的宏 观性 质与微 观 结构 所决 定
成功的药物应兼有四种属性 :安全性 ,有效性 , 稳定性 (化学和代谢的稳定性 )和可控性 。这些属 性是由药物化学结构所决定 ,寓于分子的结构之中 。
关键词 : 药物分子设计 ; 宏观性质 ; 微观结构 ; 药代动力学 ; 药效学 中图分类号 : R916 文献标识码 : A 文章编号 : 0513 - 4870 (2008) 03 - 0227 - 07
Stra tegy of molecular design of drugs: the un if ica tion of macro2properties and m icro2structures of a molecule
·述 评 ·
药学学报 Acta Pharmaceutica Sinica 2008, 43 (3) : 227 - 233
·22ຫໍສະໝຸດ Baidu·
药物分子设计的策略 : 分子的宏观性质与微观结构的统一
郭宗儒 3
(中国医学科学院 药物研究所 , 北京 100050)
摘要 : 药物与机体的相互作用 ,包含机体对药物的处置和药物对机体的作用 。机体对药物的处置 ,所进行的物 理和化学 、时间和空间的处置 ,遵循一般的规律 ,具有共性特征 ,即分子的整体和宏观性质影响药代动力学行为 。药 物对机体的作用 ,是药物分子与靶标蛋白的物理或化学结合 ,引发药理 (或毒理 )作用 ,起因于药物的特异性作用 ,是 药物分子的个性表现 ,受制于药物分子中特定的原子或基团与靶标分子在三维空间的结合 ,这种微观结构就是药效 团 。药物分子可视作宏观性质与微观结构的集合 ,统一在分子的整体结构之中 ,宏观性质决定药代和物化性质 ,微 观结构决定药理作用 。认识宏观与微观同药代与药效的内在相互关系 ,可以深化对药物作用的认识 ,指导药物分子 设计 。决定分子宏观性质的因素是相对分子质量 、水溶性 、电荷 、脂溶性 (分配性 )和极性表面积等 ,通常是由分子骨 架和整体分子所决定 ,无特异性的结构要求 ;决定活性的微观结构因素有氢键给体 、氢键接受体 、正电中心 、负电中 心 、疏水中心和芳环中心 。不同的生物活性取决于这些不同特征的组合及其空间排布 。分子的宏观性质 ,包含了微 观结构中原子和基团的贡献 ;在改变分子的结构以调整宏观性质时 ,往往影响微观结构的空间位置 。药物分子设计 的技巧是整合这两个因素成最佳配置 ,在早期研究阶段 ,应兼顾宏观性质与微观结构 ,使药效强度和选择性 、药代动 力学和药物的物理化学性质达到最佳的匹配 ,为此 ,要求表征药代的空间与药效学的选择性空间有结构交盖 。
·228·
药学学报 Acta Pharmaceutica Sinica 2008, 43 (3) : 227 - 233
p resum ed as an assembly of m acroscop ic p roperty and m icroscop ic structure, w ith the macroscop ic p roperties determ ining the absorp tion, distribution, metabolism and elim ination of drugs and the m icroscop ic structure coining pharm acological action. The know ledge of the internal relationship between macroscopy /m icroscopy and PK / PD conduces to comp rehension of drug action and guides molecular drug design, because this concep tion facilitates the identification of structural features necessary for biological response, and the determ ination of factors modulating the physico2chem ical and pharmacokinetic p roperties. The factors determ ining macro2p roperties include molecular weight, solubility, charge, lipophilicity (partition) , and polar surface area, etc. , which are destined by molecular scaffolds and /or side chain ( s) apart from pharm acophore. The features of m icro2structures contributing to specific activity contain hydrogen bonding donor and accep tor, positive and negative charge centers, hydrophobic centers and centers of aromatic rings. D ifferent combinations and spacial arrangem ents of these features determ ine the distinct activity p resented. The macro2p roperty and m icro2structure are integrated into a single molecule, and are inseparable. The macro2p roperty reflects overall contribution of atom s and group s in the m icro2structure. On the other hand, structural changes aimed to adjust m acroscop ic p roperty usually alter the relative position of the m icroscop ic structure. The goal of molecular drug design is to integrate the macroscop ic and m icroscop ic factors in op tim ized manner. In the early stage of molecular design, both macroscop ic p roperty and m icroscop ic structure should be considered to make pharmacodynam ics, pharmacokinetics, and physico2chem ical p roperties in op tim al match. Therefore, it required the existence of structural overlapp ing among accep table pharmacokinetics, visible develop ing potential and specific pharmacodynam ics. The larger the scope of overlapp ing, the higher the possibility to be a drug.
药物作为外源性物质 ,被机体视作异物 ,机体为 了保护自己免受外来物质的侵害 ,要对其进行物理 的和化学的处置 ,并在长期进化中 ,面对结构多样性 的外来物质 ,形成了具有共性的处置方式 ,遵循一般 的原则 。这种共性行为 ,表现在吸收 、分布 、体内的 生物转化 、排泄途径 、与血浆蛋白的结合 、组织贮集 等 。研究这些过程与时间的关系 ,就是药代动力学 。 机体对药物的处置 ,通常从整体的结构及其性质出 发 ,在宏观性质上作时间与空间 、物理与化学的处 置 ,一般而言 ,不拘泥分子的细微结构 。
收稿日期 : 2007211209. 3 通讯作者 Tel / Fax: 86210283155752, E2mail: zrguo@ imm. ac. cn
© 1994-2009 China Academic Journal Electronic Publishing House. All rights reserved. http://www.cnki.net
GUO Zong2ru3
( Institu te of M a teria M ed ica, Ch inese A cadem y of M ed ica l S ciences, B eijing 100050, Ch ina)
Abstract: The interaction of a drug w ith the organism involves both the disposition of a drug by the organism and the action of a drug on the organism. The disposition of various exogenous substances, including drugs, comp lies w ith general rules. The underlying physical and chem ical changes to different drugs in view of tim e and space, i. e. pharmacokinetics, share common characteristics, that is the tout ensemble of a molecule and its macroscop ic p roperties convey direct effect on the pharm acokinetic behavior as the tendency and consequence of biological evolution. The action of a drug on the organism , on the other hand, imp licates the physico2chem ical binding of a drug molecule to the target p rotein, which induces pharm acological and toxicological effects. The biological reactions, no m atter beneficial or adverse, are all specific and individual m anifestation of the drug molecule and determ ined by the interactive binding between definitive atom s or group s of the drug molecule and the macromolecular target in three2dimension. Such critical atom s, group s, or fragments responsible for the interaction reflect the m icroscop ic structures of drug molecules and are called pharmacophore. In this context, a drug molecule is