Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations
Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations
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DOI：
10.1021/acschemneuro.9b00300
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Cosconati, Sandro
中科院分区：
文献类型：
--
作者：
Bruno, Agostino;Barresi, Elisabetta;Cosconati, Sandro
转运蛋白18kda （TSPO）是一种有效的药理靶点，用于开发新的神经系统疾病治疗方法。N，N-二烷基-2-苯基吲哚-3-酰基乙醛酰胺（PIGAs）是有效的TSPO调节剂，对于治疗焦虑、星形胶质细胞丢失的中枢神经系统病变和炎症性神经病变具有潜在的治疗作用。对于这类化合物，TSPO结合亲和力与相应的功能功效之间不存在相关性。相反，它们的生物学有效性与解结合事件的动力学有关，更具体地说与停留时间（RT）有关。到目前为止，同源piga不同记录RT的结构原因仍然难以捉摸。为了了解PIGAs的不同动力学，采用增强采样分子动力学模拟研究了它们的解结合路径。这些研究结果揭示了PIGAs之间细微的结构差异如何对解结合能量学产生实质性影响。特别是，在离开TSPO结合位点的过程中，慢解离的PIGAs发现与蛋白LP1区域紧密相互作用，从而确定了较长的RT。体内研究进一步支持了这些发现，该研究表明，观察到的PIGAs的抗焦虑作用与它们对TSPO的RT相关。
Translocator protein 18 kDa (TSPO) is a validated pharmacological target for the development of new treatments for neurological disorders. N,N-Dialkyl-2-phenyl-indol-3-ylglyoxylamides (PIGAs) are effective TSPO modulators and potentially useful therapeutics for the treatment of anxiety, central nervous system pathologies featuring astrocyte loss, and inflammatory-based neuropathologies. For this class of compounds, no correlation exists between the TSPO binding affinity and the corresponding functional efficacy. Rather, their biological effectiveness correlates with the kinetics of the unbinding events and more specifically with the residence time (RT). So far, the structural reasons for the different recorded RT of congeneric PIGAs remain elusive. Here, to understand the different kinetics of PIGAs, their unbinding paths were studied by employing enhanced-sampling molecular dynamics simulations. Results of these studies revealed how subtle structural differences between PIGAs have a substantial effect on the unbinding energetics. In particular, during the egress from the TSPO binding site, slow-dissociating PIGAs find tight interactions with the protein LP1 region thereby determining a long RT. Further support to these findings was achieved by in vivo studies, which demonstrated how the anxiolytic effect observed for the inspected PIGAs correlated with their RT to TSPO.