State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4742-4. doi: 10.1016/j.bmcl.2011.06.075. Epub 2011 Jun 23.
Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification.
近年来，由于脂肪酸合酶（FAS）抑制剂在肥胖症和癌症治疗方面的潜在应用，其研发日益受到关注。本研究基于 FAS 的人 KS 结构域的首个晶体结构进行了基于药效团模型的研究。所建立的药效团模型被用作 3D 查询，从化学数据库 Specs 中检索有效的 FAS 抑制剂。进一步进行对接研究，以优化获得的命中化合物。最后，根据排名顺序和视觉检查，共选择了 28 种化合物，首先通过基于细胞系的测定进行评估。对两种 FAS 过表达癌细胞系具有良好抑制活性的 7 种化合物进一步通过基于酶的测定进行评估。发现一种具有新化学结构骨架的化合物对 FAS 具有低微摩尔抑制活性，已对其进行进一步的化学结构修饰。
