药学学报, 2011, 46(4): 361-369
引用本文:
郭宗儒. 药物的杂泛性[J]. 药学学报, 2011, 46(4): 361-369.
GUO Zong-Ru. Drug promiscuity[J]. Acta Pharmaceutica Sinica, 2011, 46(4): 361-369.

药物的杂泛性
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:

成功的药物应具备两个要素: 足够强度和选择性的药理作用, 适宜的物理化学、药代、安全和结构新颖的成药性。药物的杂泛性涉及到这两个方面。杂泛性是指一种药物与多种靶标发生相互作用, 而引起相同或不同的药理作用的现象, 药物的杂泛性是多重药理学的基础, 也是药物产生副作用和药代动力学不合理的原因。药物产生杂泛性的根源是蛋白的杂泛性, 在进化过程中, 为了结合、代谢和清除结构多样的内源和外源性物质, 蛋白具有广泛和可变的结构容纳性, 无需对每种化合物都准备特异的蛋白, 体现了受体的杂泛性。靶标蛋白具有保守性和多样性。保守性体现在折叠成二级结构的结构域比较固定和保守, 因而与配体分子的结合互有交盖, 发生交叉反应性。多样性体现在精细的结构内涵, 相似的结构域因为有不同的氨基酸序列, 功能是不同的, 体现了特异性, 因而靶标多为一专多能的蛋白。利用杂泛性以设计 (design in) 治疗复杂疾病的多靶标药物, 摒弃 (design out) 杂泛性的不利因素以完善成药性。所以认真分析和处置功过参半的杂泛性是提高药物设计成功率的重要保证, 正确预测配体的杂泛性也是分子设计的终极目标。本文对受体、酶、离子通道和细胞色素CYP450等与配体的杂泛性和药物设计的关系进行了讨论, 并简述基于受体结构和基于配体结构的预测杂泛性的方法。

关键词:   
Drug promiscuity
Abstract:

It is essential for a successful drug to possess two basic characteristics: satisfactory pharmacological action with sufficient potency and selectivity; good druggability with eligible physicochemical, pharmacokinetic and safety profiles, as well as structural novelty.  Promiscuity is defined as the property of a drug to act with multiple molecular targets and exhibit distinct pharmacological effects.  Promiscuous drugs are the basis of polypharmacology and the causes for side effects and unsuitable DMPK.  Drug promiscuity originates from protein promiscuity.  In order to accommodate, metabolize and excrete various endo- and exogenous substances, protein acquired the capability during evolution to adapt a wide range of structural diversity, and it is unnecessary to reserve a specific protein for every single ligand.  The structures of target proteins are integration of conservativity and diversity.  The former is represented by the relatively conservative domains for secondary structures folding, which leads to overlapping in ligand-binding and consequent cross-reactivity of ligands.  Diversity, however, embodies the subtle difference in structures.  Similar structural domain may demonstrate different functions due to alteration of amino acid sequences.  The phenomenon of promiscuity may facilitate the “design in” of multi-target ligands for the treatment of complicated diseases, whereas it should be appropriately handled to improve druggability.  Therefore, one of the primary goals in drug design is to scrutinize and manipulate the “merits and faults” of promiscuity.  This review discusses the application of promiscuity in drug design for receptors, enzymes, ion channels and cytochrome P450.  It also briefly describes the methods to predict ligand promiscuity based on either target or ligand structures.

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