(9RS)-ethylbiotin methyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: (9RS)-ethylbiotin methyl ester
• 英文别名: methyl 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-2-ethylpentanoate
• 化学式: C₁₃H₂₂N₂O₃S
• 分子量: 286.395
• InChiKey: LFPLODHRJJIKQR-KQFSYOIOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  92.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  D-生物素 在 六甲基磷酰三胺 、 四甲基乙二胺 、 硫酸 、 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 18.5h， 生成 (9RS)-ethylbiotin methyl ester
  参考文献：
  名称：

  Theoretical and Experimental Studies of Biotin Analogues That Bind Almost as Tightly to Streptavidin as Biotin

  摘要：

  We have used a newly developed qualitative computational approach, PROFEC (Pictorial Representation of Free Energy Changes), to visualize the areas of the ligand biotin where modifications of its structure might lead to tighter binding to the protein streptavidin. The PROFEC analysis, which includes protein flexibility and ligand solvation/desolvation, led to the suggestion that the pro-9R hydrogen atom of biotin, which is in a-position to the CO2- group, might be changed to a larger group and lead to better binding with streptavidin and avidin. Free energy calculations supported this suggestion and predicted that the methyl analogue should bind approximate to3 kcal/mol more tightly to streptavidin, with this difference coming exclusively from the relative desolvation free energy of the ligand. The PROFEC analysis further suggested little or no improvement for changing the pro-9S hydrogen atom to a methyl group, and great reduction in changing the ureido N-H groups to N-CH3. Stimulated by these results, we synthesized 9R-methylbiotin and 9S-methylbiotin, and their binding free energies and enthalpies were measured for interaction with streptavidin and avidin, respectively. In contrast to the calculated results, experiments found both 9-methylbiotin isomers to bind more weakly to streptavidin than biotin. The calculated preference for the binding of the 9R- over the 9S-stereoisomer was observed. In addition, 9-methylbiotin is considerably less soluble in water than biotin, as predicted by the calculation, and the 9R isomer is, to our knowledge, thus far the tightest binding analogue of biotin to streptavidin. Subsequently, X-ray structures of the complexes between streptavidin and both 9R- and 9S-methylbiotin were determined, and the structures were consistent with those used in the free energy calculations. Thus, the reason for the discrepancy between the calculated and experimental binding free energy does not lie in unusual binding modes for the 9-methylbiotins.

  DOI：

  10.1021/jo991846s

文献信息

• Theoretical and Experimental Studies of Biotin Analogues That Bind Almost as Tightly to Streptavidin as Biotin
  作者：Richard W. Dixon、Randall J. Radmer、Bernd Kuhn、Peter A. Kollman、Jaemoon Yang、Cesar Raposo、Craig S. Wilcox、Lisa A. Klumb、Patrick S. Stayton、Craig Behnke、Isolde Le Trong、Ronald Stenkamp

  DOI：10.1021/jo991846s

  日期：2002.3.1

  We have used a newly developed qualitative computational approach, PROFEC (Pictorial Representation of Free Energy Changes), to visualize the areas of the ligand biotin where modifications of its structure might lead to tighter binding to the protein streptavidin. The PROFEC analysis, which includes protein flexibility and ligand solvation/desolvation, led to the suggestion that the pro-9R hydrogen atom of biotin, which is in a-position to the CO2- group, might be changed to a larger group and lead to better binding with streptavidin and avidin. Free energy calculations supported this suggestion and predicted that the methyl analogue should bind approximate to3 kcal/mol more tightly to streptavidin, with this difference coming exclusively from the relative desolvation free energy of the ligand. The PROFEC analysis further suggested little or no improvement for changing the pro-9S hydrogen atom to a methyl group, and great reduction in changing the ureido N-H groups to N-CH3. Stimulated by these results, we synthesized 9R-methylbiotin and 9S-methylbiotin, and their binding free energies and enthalpies were measured for interaction with streptavidin and avidin, respectively. In contrast to the calculated results, experiments found both 9-methylbiotin isomers to bind more weakly to streptavidin than biotin. The calculated preference for the binding of the 9R- over the 9S-stereoisomer was observed. In addition, 9-methylbiotin is considerably less soluble in water than biotin, as predicted by the calculation, and the 9R isomer is, to our knowledge, thus far the tightest binding analogue of biotin to streptavidin. Subsequently, X-ray structures of the complexes between streptavidin and both 9R- and 9S-methylbiotin were determined, and the structures were consistent with those used in the free energy calculations. Thus, the reason for the discrepancy between the calculated and experimental binding free energy does not lie in unusual binding modes for the 9-methylbiotins.