Gao Dingding, Li Yingxia
School of Pharmacy, Fudan University, Shanghai 201203, China.
School of Pharmacy, Fudan University, Shanghai 201203, China.
Bioorg Med Chem. 2017 Jul 15;25(14):3780-3791. doi: 10.1016/j.bmc.2017.05.017. Epub 2017 May 10.
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer's disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein. The preliminary SAR was further explored and the binding mode with IDO1 protein was predicted by experiment along with molecular docking. Subsequent ADME properties of these active compounds were analyzed in silico, and the results showed good pharmacokinetic efficiencies. We believe this study contributes a lot to the structural diversity for the future development of highly potent IDO1 inhibitors.
吲哚胺2,3-双加氧酶1（IDO1）在色氨酸通过犬尿氨酸途径的分解代谢中起着至关重要的作用，该途径涉及包括癌症、阿尔茨海默病等多种人类疾病。在本研究中，通过基于结构的虚拟筛选，鉴定出具有1-茚酮骨架的化合物1为新型IDO1抑制剂，具有中等至良好的酶抑制活性和细胞抑制活性。此外，表面等离子体共振分析验证了化合物1与IDO1蛋白之间的直接相互作用。进一步探索了初步的构效关系，并通过实验结合分子对接预测了与IDO1蛋白的结合模式。随后对这些活性化合物的药代动力学性质进行了计算机模拟分析，结果显示出良好的药代动力学效率。我们相信这项研究为未来开发高效IDO1抑制剂的结构多样性做出了很大贡献。
