The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China.
School of Food Science and Technology, Jiangnan University, Wuxi, China.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1007-1015. doi: 10.1080/14756366.2021.1915301.
Serine palmitoyltransferase (SPT) plays the key role on catalysing the formation of 3-ketodihydrosphingosine, which is the first step of the biosynthesis of sphingolipids. SPT is linked to many diseases including fungal infection, making it a potential therapeutic target. Thus, a logical docking-based virtual screening method was used to screen selective SPT inhibitor against fungi, not human. We used myriocin-similarity database to identify compounds with good binding with fungal SPT and poor binding with homology human SPT model. Preliminary bio-assay led to the discovery of a promising inhibitor , which displayed good inhibitory activity against diversity fungi strains with MIC ranging from 0.78 to 12.5 μg/mL. could significantly reduce sphingolipids content in fungi and no effect on mouse fibroblast cell line L929. Molecular dynamics simulation depicted that SPT/ complex formed the favoured interactions. Taken together, discovery of provided valuable guide for the development of novel anti-fungal agents.
丝氨酸棕榈酰转移酶（SPT）在催化 3-酮二氢鞘氨醇形成中发挥关键作用，3-酮二氢鞘氨醇是鞘脂类生物合成的第一步。SPT 与包括真菌感染在内的许多疾病有关，使其成为一个有潜在治疗价值的靶点。因此，我们使用基于合理对接的虚拟筛选方法，筛选针对真菌而非人类的选择性 SPT 抑制剂。我们使用类霉菌素相似性数据库来鉴定与真菌 SPT 具有良好结合性且与同源人 SPT 模型结合性差的化合物。初步的生物测定导致发现了一种有前途的抑制剂，该抑制剂对多种真菌菌株表现出良好的抑制活性，最低抑菌浓度（MIC）范围为 0.78 至 12.5μg/mL。它能显著降低真菌中的鞘脂含量，而对小鼠成纤维细胞系 L929 没有影响。分子动力学模拟描述了 SPT/抑制剂复合物形成了有利的相互作用。总之，抑制剂的发现为新型抗真菌药物的开发提供了有价值的指导。
