Getting it right: modeling of pH, solvent and "nearly" everything else in virtual screening of biological targets
Getting it right: modeling of pH, solvent and "nearly" everything else in virtual screening of biological targets
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DOI：
10.1016/j.jmgm.2004.03.008
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发表时间：
2004-07-01
影响因子：
2.9
通讯作者：
Abraham, DJ
中科院分区：
文献类型：
--
作者：
Kellogg, GE;Fornabaio, M;Abraham, DJ
“做对”是指对生命系统中的所有元素（即生物大分子、配体和水分子）进行仔细建模。此外，应特别注意配体上可电离官能团和活性位点残基的质子化状态。基于经验HINT程序的计算技术被描述为：（1）计算配体结合的自由能分数； (2) 包括水在配体结合位点内部和周围的隐式和显式效应； (3) 在分子模型中纳入全局和局部 pH 值的影响。最后一点主张同时考虑许多分子模型，每个模型都有不同的质子化曲线。最近蛋白质配体系统（胰蛋白酶、凝血酶、神经氨酸酶、HIV-1 蛋白酶等）研究的数据用于说明本文中的概念。还讨论了与使用该技术和其他计算技术进行准确自由能预测相关的实验因素。 (C) 2004 Elsevier Inc. 保留所有权利。
"Getting it right" refers to the careful modeling of all elements in the living system, i.e. biological macromolecules, ligands and water molecules. In addition, careful attention should be paid to the protonation state of ionizable functional groups on the ligands and residues at the active site. Computational technology based on the empirical HINT program is described to: (1) calculate free energy scores for ligand binding; (2) include the implicit and explicit effects of water in and around the ligand binding site; and (3) incorporate the effects of global and local pH in molecular models. This last point argues for the simultaneous consideration of a number of molecular models, each with different protonation profiles. Data from recent studies of protein-ligand systems (trypsin, thrombin, neuraminidase, HIV-1 protease and others) are used to illustrate the concepts in the paper. Also discussed are experimental factors related to accurate free energy predictions with this and other computational technologies. (C) 2004 Elsevier Inc. All rights reserved.