Curr Top Med Chem. 2013;13(1):2-4. doi: 10.2174/1568026611313010002.
Allosteric drugs bind to sites which are usually less conserved evolutionarily as compared to orthosteric sites. As such, they can discriminate between closely related proteins, have fewer side effects, and a consequent lower concentration can convey a lesser likelihood of receptor desensitization. However, an allosteric mode of action may also make the results of preclinical and animal experiments less predictive. The sensitivity of the allosteric consequences to the environment further increases the importance of accounting for patient population diversity. Even subtle differences in protein sequence, in cellular metabolic states or in target tissues, can result in different outcomes. This mini-hot-topic issue of CTMC showcases some successes and challenges of allosteric drug development through the examples of seventransmembrane (GPCR), AMPA, NMDA and metabotropic glutamate receptors, as well as the morpheein model of allosterism involved in inherent metabolic errors. Finally, the development of allo-network drugs, which are allosteric drugs acting indirectly on the neighborhood of the pharmacological target in protein-protein interaction or signaling networks, is described.
变构药物与变构位点结合，与变构位点相比，这些变构位点在进化上通常不太保守。因此，它们可以区分密切相关的蛋白质，副作用较少，因此浓度较低不太可能导致受体脱敏。然而，变构作用模式也可能使临床前和动物实验的结果预测性降低。变构后果对环境的敏感性进一步增加了考虑患者人群多样性的重要性。即使蛋白质序列、细胞代谢状态或靶组织中的细微差异，也可能导致不同的结果。本期 CTMC 迷你热点问题通过七跨膜 (GPCR)、AMPA、NMDA 和代谢型谷氨酸受体的例子，以及涉及固有代谢错误的变构体模型，展示了变构药物开发的一些成功和挑战。最后，描述了变构网络药物的开发，变构网络药物是通过蛋白质-蛋白质相互作用或信号网络中药物靶点附近的间接作用发挥变构作用的药物。
