Epik:: a software program for pK a prediction and protonation state generation for drug-like molecules
Epik:: a software program for pK a prediction and protonation state generation for drug-like molecules
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DOI：
10.1007/s10822-007-9133-z
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Uchimaya, Makoto
中科院分区：
文献类型：
--
作者：
Shelley, John C.;Cholleti, Anuradha;Uchimaya, Makoto
Epik 是一个用于预测类药物分子 pK(a) 值的计算机程序。 Epik 可以将此功能与互变异构技术结合使用，以调整类药小分子的质子化状态，从而自动生成一种或多种最可能的形式，用于进一步的分子建模研究。许多药物化学物质可以与其环境交换质子，导致各种电离和互变异构状态，统称为质子化状态。药物的质子化状态会影响其溶解度和膜渗透性。在建模中，配体的质子化状态也会影响分子的构象预测，以及基于蛋白质-配体相互作用的结合模式和配体亲和力的预测。尽管质子化态很重要，但药物开发中使用的许多候选分子数据库并未存储有关最可能质子化态的可靠信息。 Epik 足够快速和准确，可以处理大型药物分子数据库来提供此信息。采用了多项新技术。对完善的 Hammett 和 Taft 方法的扩展用于 pK(a) 预测，即内消旋体标准化、电荷抵消和电荷扩散，以使预测结果反映分子本身的性质，而不仅仅是输入中使用的特定路易斯结构。此外，还采用了一种新的迭代技术来生成、排序和剔除所生成的质子化态。
Epik is a computer program for predicting pK(a) values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pK(a) prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.