Department of Chemistry and Biophysics, University of Michigan, Ann Arbor, Michigan, USA.
Nat Chem Biol. 2011 Jun 26;7(8):553-9. doi: 10.1038/nchembio.596.
Current approaches used to identify protein-binding small molecules are not suited for identifying small molecules that can bind emerging RNA drug targets. By docking small molecules onto an RNA dynamic ensemble constructed by combining NMR spectroscopy and computational molecular dynamics, we virtually screened small molecules that target the entire structure landscape of the transactivation response element (TAR) from HIV type 1 (HIV-1). We quantitatively predict binding energies for small molecules that bind different RNA conformations and report the de novo discovery of six compounds that bind TAR with high affinity and inhibit its interaction with a Tat peptide in vitro (K(i) values of 710 nM-169 μM). One compound binds HIV-1 TAR with marked selectivity and inhibits Tat-mediated activation of the HIV-1 long terminal repeat by 81% in T-cell lines and HIV replication in an HIV-1 indicator cell line (IC(50) ∼23.1 μM).
目前用于鉴定与蛋白质结合的小分子的方法并不适用于鉴定能够与新兴 RNA 药物靶点结合的小分子。通过将小分子对接至由 NMR 光谱和计算分子动力学相结合构建的 RNA 动态组合体上，我们从 HIV-1 中针对整个转录激活反应元件 (TAR) 结构景观进行了虚拟筛选。我们对与不同 RNA 构象结合的小分子的结合能进行了定量预测，并报告了六个高亲和力结合 TAR 的化合物的从头发现，它们在体外抑制了 TAR 与 Tat 肽的相互作用 (K(i) 值为 710 nM-169 μM)。一种化合物对 HIV-1 TAR 具有明显的选择性，在 T 细胞系中抑制 Tat 介导的 HIV-1 长末端重复的激活达 81%，并在 HIV-1 指示细胞系中抑制 HIV 复制 (IC(50) ∼23.1 μM)。
