Institute of Theoretical Chemistry, Faculty of Chemistry, University of Vienna, Währinger Str. 17, 1090 Vienna Austria.
Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Währinger Str. 42, 1090 Vienna Austria.
J Phys Chem Lett. 2023 Nov 23;14(46):10333-10339. doi: 10.1021/acs.jpclett.3c02655. Epub 2023 Nov 9.
Serotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to the development of debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whose - and -isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of the -isomer, which blocks more efficiently the hSERT conformational cycle, leading to serotonin uptake.
血清素是一种调节多种神经过程的必需介质，其失调与衰弱性神经疾病的发展有关。特别是，人类血清素转运蛋白（hSERT）在通过允许血清素再摄取来完成突触神经循环方面起着至关重要的作用。其抑制作用尤其具有吸引力，特别是作为抗抑郁综合征的药理学靶点。在这里，我们通过使用长程分子动力学模拟分析了一种分子光开关的行为，该分子光开关的 - 和 - 异构体对 hSERT 的抑制作用不同。特别是，我们证明了 - 异构体具有更高抑制能力的结构和分子基础，它更有效地阻止了 hSERT 的构象循环，从而导致血清素摄取。
