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Drug promiscuity
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- Author:
- No author available
- Journal Title:
- ACTA PHARMACEUTICA SINICA
- Issue:
- 4
- DOI:
- No doi available
- Key Word:
- 药物杂泛性;药物设计;多靶标作用;成药性
Abstract： 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,相似的结构域冈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.
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