Lei Beilei, Heng Ningjuan, Dang Xiaoxue, Liu Jiyuan, Yao Xiaojun, Zhang Cunli
Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, China.
Mol Biosyst. 2017 Jun 27;13(7):1364-1369. doi: 10.1039/c7mb00214a.
Brassinosteroids (BRs) are a class of plant steroid hormones that play indispensable roles in cell elongation, division and plant development. To date, the numerous synthesis of BRs analogs and structure-activity relationship investigations have clearly revealed the key substituent groups relevant to the steroidal activity of BRs. However, due to the limited chemical space studied, the efforts for alternative non-steroidal compounds have produced no remarkable results. To identify potentially non-steroidal BR mimics in this study, vital interacting pharmacophore features were extracted starting from several complex structures of BRs that bound with the receptor Brassinosteroid-Insentive 1 (BRI1) and co-receptor BRI1-associated kinase 1 (BAK1), which were characterized and merged into one comprehensive pharmacophore model. In silico screening of a commercial compound database was carried out by combing pharmacophore modeling, molecular docking and visual analysis. Finally, six non-steroidal molecules were identified and subjected to the in vivo radish hypocotyl elongation assay. As a positive control, the hypocotyls elongation for the naturally most active BR brassinolide (BL) is 152 ± 3% at 100 nM. Moreover, two candidates (4 and 6) show good BRs-like activity with the hypocotyls elongation of 143 ± 1% and 128 ± 3% at the same dose, respectively. Most remarkably, compounds 4 and 6, which have different structures, are predicted to share similar binding modes and proven to exhibit potential BRs-like activity. The two compounds obtained could be valuable leads for the development of BRs-like plant growth regulators.
油菜素甾体类化合物（BRs）是一类植物甾体激素，在细胞伸长、分裂和植物发育中发挥着不可或缺的作用。迄今为止，大量的BRs类似物合成及构效关系研究已清楚地揭示了与BRs甾体活性相关的关键取代基。然而，由于所研究的化学空间有限，寻找替代性非甾体化合物的努力并未产生显著成果。在本研究中，为了鉴定潜在的非甾体BR模拟物，从与受体油菜素甾体类化合物不敏感1（BRI1）和共受体BRI1相关激酶1（BAK1）结合的几种BRs复杂结构中提取重要的相互作用药效团特征，对其进行表征并合并为一个综合药效团模型。通过结合药效团建模、分子对接和可视化分析，对一个商业化合物数据库进行了虚拟筛选。最后，鉴定出6种非甾体分子，并对其进行了体内萝卜下胚轴伸长试验。作为阳性对照，天然活性最高的BR油菜素内酯（BL）在100 nM时下胚轴伸长率为152±3%。此外，两种候选物（4和6）表现出良好的BRs样活性，在相同剂量下下胚轴伸长率分别为143±1%和128±3%。最值得注意的是，结构不同的化合物4和6被预测具有相似的结合模式，并被证明具有潜在的BRs样活性。所获得的这两种化合物可能是开发BRs样植物生长调节剂的有价值先导化合物。
