靶向 miRNA-mRNA 解除 mRNA 抑制的小分子化合物发现新策略

调控相关miRNA的作用机制，是目前治疗一系列复杂疾病的关键问题。目前仍没有一个有效的方法可以针对miRNA-mRNA设计出靶向的小分子化合物。因此，设计出可以靶向miRNA-mRNA，解除mRNA抑制的化合物发现方法尤为重要。本研究拟检索文献，专利，数据库，得到迄今为止最全面的RNA -小分子化合物信息。通过机器学习的方法，建立起RNA-小分子化合物关系模型，并利用miRNA-mRNA的空间结构信息进行的自由能计算。以申报人团队在前期研究中的骨质疏松为例，通过计算，可以得到与miRNA-214-ATF4 mRNA复合体结合的潜在小分子化合物。通过miRNA214骨质疏松体外实验模型，验证建立的靶向miRNA-mRNA化合物发现方法的可靠性。

RNA regulation technology suppresses the RNA function by using RNA interference (RNAi) . Since RNAi is easy to degradate, the druggability of RNAi is short. There is still no effective methods for small molecule compound targeting miRNA -mRNA. To address the issue, we constructed a small molecule discovery web server for targeting miRNA-mRNA interaction. The web server contained two components, the database screening and 3D molecular dynamic simulation. Firstly, the web server could facilitate screening a small molecule-RNA motif database to generate a list of candidate small molecules targeting the intermolecular area between two query RNAs. Secondly, the web server could generate another list of small molecules by calculating the binding energy of AGO-miRNA-mRNA-small molecule complex. The intersection of the two lists were regarded as selective and credible small molecules targeting miRNA-mRNA interaction. To test the above method, we used the miRNA-214 targeting ATF4 mRNA model to screen candidate small molecules targeting miRNA-214-ATF4 mRNA, which can rescue inhibition of ATF4 mRNA translation to promote osteoblast activity in vitro.