通过开发基于蛋白质的药效团发现新型选择性 5-羟色胺再摄取抑制剂。
Discovery of novel selective serotonin reuptake inhibitors through development of a protein-based pharmacophore.
机构信息
Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.
出版信息
J Chem Inf Model. 2011 Sep 26;51(9):2417-26. doi: 10.1021/ci200280m. Epub 2011 Sep 2.
Abstract
The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the X-ray coordinates of the leucine transporter LeuT, a bacterial NSS homologue. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development.
摘要
血清素转运体（SERT）是神经递质钠离子转运体（NSS）家族的一员，负责将血清素从突触间隙中再摄取，以维持神经递质的稳态。SERT 已被确立为治疗焦虑和抑郁的重要靶点。由于缺乏高分辨率的晶体结构，因此基于细菌 NSS 同源物亮氨酸转运蛋白 LeuT 的 X 射线坐标构建了 SERT 的计算模型。该模型用于开发基于 SERT 结构的药效团。使用生成的 SERT 计算模型对小分子结构文库进行虚拟筛选（VS），得到了具有不同骨架的候选配体。对 VS 命中物的药理学分析鉴定出两种 SERT 选择性化合物，它们可能是进一步开发 SERT 相关药物的先导化合物。
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