Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Center for Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, USA.
Biomolecules. 2024 Oct 12;14(10):1287. doi: 10.3390/biom14101287.
MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this key protein. Genetic algorithm-based computational design and the five-eight step synthesis of three molecules led to ligands with affinities in the range of 1-3 µM, a 20-60-fold improvement over literature reports. The design and synthesis strategies, coupled with the structure-dependent gain or loss in affinity, afford the deduction of principles that should guide the design of advanced probes of MDA-9/Syntenin.
MDA-9/Syntenin，一种关键的支架蛋白和分子枢纽，参与多种细胞信号反应，已被证明是设计和发现小分子探针的具有挑战性的目标。在本文中，我们报告了这种关键蛋白质的小分子配体的设计和合成。基于遗传算法的计算设计和五到八步合成三个分子，得到了亲和力在 1-3µM 范围内的配体，比文献报道提高了 20-60 倍。设计和合成策略，以及与结构相关的亲和力的得失，提供了应该指导 MDA-9/Syntenin 的高级探针设计的原则的推论。
