Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors
Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors
复制标题
新型 AKR1C3 抑制剂 6-氨基-4-苯基-1,4-二氢吡喃并[2,3-c]吡唑-5-甲腈的筛选、合成、晶体结构和分子基础
DOI：
10.1016/j.bmc.2018.10.044
复制
发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Wu, Deyan
中科院分区：
文献类型：
--
作者：
Zheng, Xuehua;Jiang, Zan;Wu, Deyan
AKR1C3是去势抵抗性前列腺癌的一个有前途的治疗靶点。本文中，对内部文库的评价发现取代的吡喃吡唑作为AKR1C3抑制剂的新型支架。初步的SAR探索确定其衍生物19d为最有前途的化合物，在23个合成的分子中，IC 50为0.160 μ M。晶体结构研究表明，吡喃吡唑骨架的结合模式与目前的抑制剂不同。C4-苯基取代基上的羟基、甲氧基和硝基一起将抑制剂锚在含氧阴离子位点，而支架的核心显著增大但部分占据具有丰富氢键相互作用的SP口袋。引人注目的是，抑制剂经历构象变化以适应AKR1C3及其同源蛋白AKR1C1。我们的研究结果表明，在合理设计选择性AKR1C3抑制剂时，应同时考虑受体和抑制剂的构象变化。通过分子动力学模拟得到的详细结合特征有助于最终阐明6-氨基-4-苯基-1，4-二氢吡喃并[2，3-c]吡唑-5-甲腈类化合物作为AKR1C3抑制剂的分子基础，为今后合理设计和优化抑制剂结构提供了理论依据。
AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of inhouse library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 mu M among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.