(R)-2-(1-carboxy-2-(naphthalen-2-yl)ethyl)-1,3-dioxoisoindoline-5-carboxylic acid | 1014090-34-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (R)-2-(1-carboxy-2-(naphthalen-2-yl)ethyl)-1,3-dioxoisoindoline-5-carboxylic acid
• 英文别名: 2-[(1R)-1-carboxy-2-naphthalen-2-ylethyl]-1,3-dioxoisoindole-5-carboxylic acid
• CAS: 1014090-34-6
• 化学式: C₂₂H₁₅NO₆
• 分子量: 389.364
• InChiKey: XRVAOQLAEMOSRB-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  D-3-(2-萘基)-丙氨酸 、 偏苯三酸酐 以 二乙二醇二甲醚 为溶剂， 反应 0.17h， 以59%的产率得到(R)-2-(1-carboxy-2-(naphthalen-2-yl)ethyl)-1,3-dioxoisoindoline-5-carboxylic acid
  参考文献：
  名称：

  Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase

  摘要：

  High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against P-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent- sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 mu M. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens.

  DOI：

  10.1021/jm701500e

文献信息

• Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase
  作者：Kerim Babaoglu、Anton Simeonov、John J. Irwin、Michael E. Nelson、Brian Feng、Craig J. Thomas、Laura Cancian、M. Paola Costi、David A. Maltby、Ajit Jadhav、James Inglese、Christopher P. Austin、Brian K. Shoichet

  DOI：10.1021/jm701500e

  日期：2008.4.1

  High-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against P-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent- sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 mu M. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens.