Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of as a better Des 1 inhibitor (IC = 700 nM) than and , the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of .

中文翻译：

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靶向二氢神经酰胺去饱和酶 1 (Des1)：具有刚性支架的神经酰胺类似物的合成、抑制测定和 AlphaFold2 辅助的结构见解揭示了环丙烯酮 PR280 作为一种有效的抑制剂

二氢神经酰胺去饱和酶 1 (Des1) 催化二氢神经酰胺中 CC 双键的形成以提供神经酰胺。 Des1 的抑制与细胞周期停滞和程序性细胞死亡有关。 Des1晶体结构以及密切同系物的缺乏阻碍了对其抑制机制的详细了解，并难以设计新的抑制剂，从而使Des1成为战略目标。根据之前的结构活性研究，设计了不同的含有刚性支架的神经酰胺。这些化合物作为 Des1 抑制剂的合成和评估允许鉴定为比当前参考抑制剂更好的 Des 1 抑制剂 (IC = 700 nM)。这种环丙烯酮神经酰胺通过 6 步合成获得，总产率为 24%。 AlphaFold2 最近预测的 Des1 高度可信的 3D 结构，作为对已知 Des1 抑制剂和我们在本研究中合成的神经酰胺衍生物进行对接研究的基础。为此目的，之前构建了完整的全蛋白结构。这项研究使我们能够更好地了解 Des1 抑制活性的关键配体-酶相互作用。此外，它还揭示了 的抑制机制。