Bohacek Regine, Boosalis Michael S, McMartin Colin, Faller Douglas V, Perrine Susan P
Boston De Novo Design, 50 Commonwealth Ave, Boston, MA 02116, USA.
Chem Biol Drug Des. 2006 May;67(5):318-28. doi: 10.1111/j.1747-0285.2006.00386.x.
Pharmacologic reinduction of the developmentally silenced fetal (gamma) globin genes has been achieved in hemoglobinopathy patients using short chain fatty acid derivatives, with therapeutic effects. However, higher-potency inducers than are available in currently identified short chain fatty acid derivatives are desirable for long-term use. Using several short-chain fatty acids with established gamma-globin induction activity, a pharmacophore template was constructed with the TFIT module of the flo software and used to select several new candidate compounds, three of which exhibited significant activity in a gamma-globin gene reporter transcriptional assay which detects only strong inducers. The data were used to construct a new pharmacophore and a 'pseudo' receptor around it. Six hundred and thirty low-molecular weight compounds were docked into this receptor model. Of 26 compounds selected and tested in functional assays, two compounds showed activity >500% over control levels and two had activity 200% over control range, significantly more active than previously identified short chain fatty acid derivative fetal globin gene inducers. Three compounds had less activity; the remainder showed moderate activity. These findings demonstrate the feasibility of using iterative construction of pharmacophores, pseudo-binding site modeling, and virtual screening to identify small molecules with the ability to induce transcription of specific target genes, for potential therapeutics.
使用短链脂肪酸衍生物已在血红蛋白病患者中实现了发育沉默的胎儿（γ）珠蛋白基因的药理学再诱导，并产生了治疗效果。然而，长期使用需要比目前已确定的短链脂肪酸衍生物更高效的诱导剂。利用几种具有既定γ-珠蛋白诱导活性的短链脂肪酸，用flo软件的TFIT模块构建了一个药效团模板，并用于筛选几种新的候选化合物，其中三种在仅检测强诱导剂的γ-珠蛋白基因报告转录测定中表现出显著活性。这些数据被用于构建一个新的药效团及其周围的“伪”受体。将630种低分子量化合物对接至该受体模型中。在功能测定中选择并测试的26种化合物中，两种化合物的活性比对照水平高500%以上，两种化合物的活性比对照范围高200%，其活性明显高于先前确定的短链脂肪酸衍生物胎儿珠蛋白基因诱导剂。三种化合物活性较低；其余化合物表现出中等活性。这些发现证明了使用药效团的迭代构建、伪结合位点建模和虚拟筛选来识别具有诱导特定靶基因转录能力的小分子用于潜在治疗的可行性。
