甲基对蛋白-配体结合的影响。
Methyl effects on protein-ligand binding.
机构信息
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
出版信息
J Med Chem. 2012 May 10;55(9):4489-500. doi: 10.1021/jm3003697. Epub 2012 Apr 23.
Abstract
The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.
摘要
考察了在先导化合物中添加一个甲基对生物活性的影响。对超过 2000 个案例的文献分析表明，有 8%的频率会发现活性提高 10 倍或更多，而提高 100 倍的情况则是每 200 个事件中有 1 个。对后一类中的 4 个案例进行了深入分析，以阐明蛋白质-配体结合、水分子分布和构象能变化的任何异常方面。分析包括 p38α MAP 激酶、ACK1、PTP1B 和凝血酶抑制剂系列中进行的 Monte Carlo/自由能微扰 (MC/FEP) 计算。在芳环的邻位引入甲基可以特别有效地通过诱导有利的构象变化来提高活性。活性的最大提高来自于将构象变化与将甲基基团埋藏在蛋白质的疏水区结合起来。
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