Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in catabolism of tryptophan via the kynurenine pathway, which plays a pivotal role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for many diseases, such as breast cancer, lung cancer, colon cancer, prostate cancer, etc. In this study, docking-based virtual screening and bioassays were conducted to identify novel inhibitors of IDO1. The cellular assay demonstrated that 24 compounds exhibited potent inhibitory activity against IDO1 at micromolar level, including 8 compounds with IC₅₀ values below 10 μM and the most potent one (compound 1) with IC₅₀ of 1.18 ± 0.04 μM. Further lead optimization based on similarity searching strategy led to the discovery of compound 28 as an excellent inhibitor with IC₅₀ of 0.27 ± 0.02 μM. Then, the structure–activity relationship of compounds 1, 2, 8 and 14 analogues is discussed. The interaction modes of two compounds against IDO1 were further explored through a Python Based Metal Center Parameter Builder (MCPB.py) molecular dynamics simulation, binding free energy calculation and electrostatic potential analysis. The novel IDO1 inhibitors of compound 1 and its analogues could be considered as promising scaffold for further development of IDO1 inhibitors.

吲哚胺 2,3-双加氧酶 1 (IDO1) 是一种含血红素的酶，通过犬尿氨酸途径催化色氨酸分解代谢的第一步和限速步骤，在 T 细胞的增殖和分化中起关键作用。IDO1 已被证明是许多疾病的有吸引力的靶点，如乳腺癌、肺癌、结肠癌、前列腺癌等。在这项研究中，进行了基于对接的虚拟筛选和生物测定来识别 IDO1 的新型抑制剂。细胞试验表明，24 种化合物在微摩尔水平上表现出对 IDO1 的有效抑制活性，其中 8 种化合物的 IC ₅₀值低于 10 μM，最有效的一种化合物（化合物 1）具有 IC ₅₀1.18 ± 0.04 μM。基于相似性搜索策略的进一步先导优化导致发现化合物 28 作为优秀的抑制剂，IC ₅₀为 0.27 ± 0.02 μM。然后，讨论了化合物 1、2、8 和 14 类似物的构效关系。通过基于 Python 的金属中心参数生成器 (MCPB.py) 分子动力学模拟、结合自由能计算和静电势分析，进一步探索了两种化合物对 IDO1 的相互作用模式。化合物1及其类似物的新型IDO1抑制剂可被认为是进一步开发IDO1抑制剂的有前途的支架。