Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Senior Vocational School, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2018 May 10;151:389-400. doi: 10.1016/j.ejmech.2018.03.065. Epub 2018 Mar 27.
Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound α-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than α-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates.
酸性鞘磷脂酶 (ASM) 已被证明参与许多生理过程，成为有前途的药物靶点。在这项研究中，我们构建了 ASM 抑制剂的基于配体的药效团模型，并应用该模型对已知的 ASM 抑制剂 α-倒捻子素进行了优化。设计并评估了 23 种化合物对 ASM 的抑制作用，其中 10 种化合物比 α-倒捻子素更有效。高命中率证实了所提出的模型非常有效和实用。最有效的化合物 1c 被发现选择性和竞争性地抑制酶，并以剂量依赖的方式抑制神经酰胺的产生。此外，1c 表现出良好的抗凋亡和抗炎活性。通过对接模拟发现了与关键残基和 Zn 辅因子的相互作用。这些结果为进一步开发有效的 ASM 抑制剂和药物候选物提供了有希望的先导化合物和重要指导。
