Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors
Effective Virtual Screening Strategy toward heme-containing proteins: Identification of novel IDO1 inhibitors
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针对含血红素蛋白的有效虚拟筛选策略：新型 IDO1 抑制剂的鉴定
DOI：
10.1016/j.ejmech.2019.111750
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Yisheng Lai
中科院分区：
文献类型：
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作者：
Yi Zou;Yue Hu;Ge Shushan;Zheng Yingbo;Li Yuezhen;Wen Liu;Wenjie Guo;Yihua Zhang;Qiang Xu;Yisheng Lai
利用计算方法开发占据血红素结合位点的小分子仍然是一项具有挑战性的任务，因为很难表征含血红素蛋白中血红素-配体相互作用。吲哚胺2，3-双加氧酶1（IDO 1）是一种细胞内含血红素的双加氧酶，与癌症的免疫抑制作用有关。以IDO 1为例，本文报道了一种结合虚拟筛选（VS）策略，包括基于高特异性血红素结合基团（HmBG）的药效团筛选和级联分子对接，以确定新的IDO 1抑制剂。共得到四个命中化合物，并显示出与血红素铁配位位点的适当结合。进一步的结构优化产生了一种有前途的化合物S18-3，其通过激活宿主的免疫系统在携带已建立的CT 26肿瘤的BALB/c小鼠中发挥了有效的抗肿瘤功效。这些结果表明，S18-3值得进一步研究，以评估其干预癌症的潜力。此外，我们的研究还揭示了一种新的基于计算机的策略，用于在短时间内识别血红素蛋白的潜在调节剂。
Developing small molecules occupying the heme-binding site using computational approaches remains a challenging task because it is difficult to characterize heme-ligand interaction in heme-containing protein. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing dioxygenase which is associated with the immunosuppressive effects in cancer. With IDO1 as an example, herein we report a combined virtual screening (VS) strategy including high-specificity heme-binding group (HmBG)-based pharmacophore screening and cascade molecular docking to identify novel IDO1 inhibitors. A total of four hit compounds were obtained and showed proper binding with the heme iron coordinating site. Further structural optimization led to a promising compound S18-3, which exerted potent anti-tumor efficacy in BALB/c mice bearing established CT26 tumors by activating the host's immune system. These results suggest that S18-3 merits further study to assess its potential for the intervention of cancer. Furthermore, our study also unveils a novel in silico-based strategy for identifying potential regulators for hemeproteins within short timeframe.