Costa Barbara, Taliani Sabrina, Da Pozzo Eleonora, Barresi Elisabetta, Robello Marco, Cavallini Chiara, Cosconati Sandro, Da Settimo Federico, Novellino Ettore, Martini Claudia
Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
DiSTABiF, University of Campania Luigi Vanvitelli, 81100, Caserta, Italy.
ChemMedChem. 2017 Aug 22;12(16):1275-1278. doi: 10.1002/cmdc.201700220. Epub 2017 Jun 22.
Targeting the biosynthetic pathway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligands may be a viable therapeutic approach for a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between binding affinity and in vitro steroidogenic efficacy has limited the identification of lead compounds by traditional affinity-based drug discovery strategies. Our recent research indicates that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends in the target, namely its residence time (RT). The assessment of this kinetic parameter during the in vitro characterization of compounds appears mandatory in order to obtain structure-efficacy relationships suitable for the future development of novel molecules with promising pharmacological properties.
用特定的18 kDa转位蛋白（TSPO）配体靶向神经活性甾体的生物合成途径可能是治疗多种神经退行性疾病和神经精神疾病的一种可行治疗方法。然而，结合亲和力与体外甾体生成功效之间缺乏相关性，限制了通过传统的基于亲和力的药物发现策略来鉴定先导化合物。我们最近的研究表明，强效甾体生成TSPO配体功效的关键因素不是结合亲和力本身，而是化合物在靶点停留的时间，即其驻留时间（RT）。在化合物的体外表征过程中评估这一动力学参数似乎是必要的，以便获得适合未来开发具有良好药理特性的新分子的构效关系。
