Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Trends Neurosci. 2016 Dec;39(12):830-839. doi: 10.1016/j.tins.2016.09.008. Epub 2016 Oct 25.
Currently, drug discovery focusses only on quantifying pharmacological parameters, sometimes including binding kinetics, of drug candidates. For a complete understanding of a drug's desired binding kinetics, the kinetics of both the target and its endogenous ligands should be considered. This is because the release and binding kinetics of endogenous ligands in addition to receptor internalization rates are significant contributors to drug-target interactions. Here, we discuss the kinetic profile of three neuropeptides and their receptors; gonadotropin-releasing hormone receptor (GnRHR), neuropeptide Y receptors, and corticotropin-releasing factor receptor 1 (CRFR). These three examples provide new insights into the importance of kinetic profiles which could improve the understanding of desired drug-target binding kinetics and advance drug discovery for various neurological and psychiatric illnesses.
目前，药物发现仅专注于量化候选药物的药理学参数，有时还包括结合动力学。为了全面了解药物的预期结合动力学，应该考虑药物靶标及其内源性配体的动力学。这是因为除了受体内化率之外，内源性配体的释放和结合动力学也是药物-靶标相互作用的重要贡献者。在这里，我们讨论了三种神经肽及其受体；促性腺激素释放激素受体 (GnRHR)、神经肽 Y 受体和促肾上腺皮质激素释放因子受体 1 (CRFR1) 的动力学特征。这三个例子提供了关于动力学特征重要性的新见解，这可能有助于提高对预期药物-靶标结合动力学的理解，并推进各种神经和精神疾病的药物发现。
