Methyl effects on protein-ligand binding.
Methyl effects on protein-ligand binding.
复制标题
甲基对蛋白质 - 配体结合的影响。
DOI：
10.1021/jm3003697
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发表时间：
2012-05-10
影响因子：
7.3
通讯作者：
Jorgensen, William L.
中科院分区：
文献类型：
--
作者：
Leung, Cheryl S.;Leung, Siegfried S. F.;Tirado-Rives, Julian;Jorgensen, William L.
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 ten 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.
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影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
5.5
作者：
Johansson, Mikael P.;Olsen, Jeppe
通讯作者：
Olsen, Jeppe
影响因子：
5.5
作者：
Jorgensen, William L.;Thomas, Laura L.
通讯作者：
Thomas, Laura L.
影响因子：
7.3
作者：
ANDREWS, PR;CRAIK, DJ;MARTIN, JL
通讯作者：
MARTIN, JL
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML