Biological Research Centre, Institute of Biochemistry, Eötvös Loránd Research Network (ELKH), H-6726 Szeged, Hungary.
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary.
Int J Mol Sci. 2021 Jul 29;22(15):8112. doi: 10.3390/ijms22158112.
Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.
西格玛-1 受体（S1R）是一种细胞内的、多功能的、配体操纵的蛋白质，也作为伴侣蛋白发挥作用。它被认为是几种病理状态下的多效性药物靶点。激动剂和拮抗剂结合受体结构的发表为基于受体的计算机药物设计铺平了道路。然而，最近关于这个主题的研究没有关注到激动剂和拮抗剂结合的结构差异。在这项工作中，我们开发了一种新的基于集合 docking 的虚拟筛选方案，利用激动剂和拮抗剂结合的 S1R 结构。该方案用于筛选我们的内部化合物库。通过竞争性放射性配体结合测定，测定了 40 种评分最高的化合物与 S1R 的结合亲和力，并测定了最佳 S1R 结合物的 sigma-2 受体（S2R）亲和力。这样，鉴定了三种新型高亲和力 S1R 配体，其中一种表现出显著的 S1R/S2R 选择性。
