Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Lyon, France.
Molecular Microbiology and Structural Biochemistry, UMR 5086, Université de Lyon, CNRS, Lyon, France.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2121821. doi: 10.1080/14756366.2022.2121821.
The mitochondrial voltage-dependent anion channel 1 (VDAC1) plays a central role in metabolism and apoptosis, which makes it a promising therapeutic target. Nevertheless, molecular mechanisms governing VDAC1 functioning remain unclear. Small-molecule ligands specifically interacting with the channel provide an attractive way of exploring its structure-function relationships and can possibly be used as founding stones for future drug-candidates. While around 30 VDAC1 ligands have been identified over the years, various techniques have been used by research teams, making a fair and direct comparison between compounds impossible. To tackle this issue, we performed ligand-binding assays on a representative set of seventeen known VDAC1 ligands using nano-differential scanning fluorimetry and microscale thermophoresis. While all the compounds have been confirmed as VDAC1 ligands by at least one method, combining both technologies lead to the selection of four molecules (cannabidiol, curcumin, DIDS and VBIT4) as chemical starting points for future design of VDAC1 selective ligands.
线粒体电压依赖性阴离子通道 1（VDAC1）在代谢和细胞凋亡中发挥着核心作用，使其成为一个很有前途的治疗靶点。然而，调控 VDAC1 功能的分子机制仍不清楚。与通道特异性相互作用的小分子配体为探索其结构-功能关系提供了一种有吸引力的方法，并且可能被用作未来候选药物的基石。虽然多年来已经鉴定出了约 30 种 VDAC1 配体，但不同的研究团队使用了各种技术，使得化合物之间无法进行公平和直接的比较。为了解决这个问题，我们使用纳米差异扫描荧光法和微尺度热泳法对一组具有代表性的十七种已知 VDAC1 配体进行了配体结合测定。虽然所有化合物都至少通过一种方法被证实为 VDAC1 配体，但两种技术的结合导致选择了四种分子（大麻二酚、姜黄素、DIDS 和 VBIT4）作为未来设计 VDAC1 选择性配体的化学起点。
