Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
J Comput Aided Mol Des. 2013 May;27(5):403-17. doi: 10.1007/s10822-013-9653-7. Epub 2013 May 3.
In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities. The pK a values of the BACE-1 acidic residues deviate substantially from the estimates for model compounds in solution and display a ligand dependent variability, especially in the case of the catalytic Asp dyad residues. This outcome should have a strong bearing on the design of protocols for docking based BACE-1 screening campaigns. Finally, we were able to find an explanation for the poor docking success rate of some fragments based on the availability of anchoring points, a rationale that could help to improve hit rates in BACE-1 screening campaigns.
在这项工作中，我们提出了一种估计 pH 值对 BACE-1 对接性能影响的方案，该方案提供了抑制剂的电荷状态以及给定 pH 值下蛋白质中所有可离子化残基的质子化状态。据我们所知，这是第一个报告预测 BACE-1 配体对接构象的方案，不仅可以预测大多数晶体结构在中性 pH 值下的构象，还可以预测酶的最佳 pH 值（在酸性范围内），大多数 BACE-1 结合亲和力测定都是在这个 pH 值下进行的。我们已经将该方案应用于一组 23 个片段样 BACE-1 配体，这些配体的结合亲和力跨越了四个数量级。BACE-1 酸性残基的 pK a 值与溶液中模型化合物的估计值有很大差异，并且表现出配体依赖性变异性，特别是在催化天冬氨酸二联体残基的情况下。这一结果应该对基于对接的 BACE-1 筛选方案的设计有很大的影响。最后，我们能够根据锚定点的可用性，为一些片段的差对接成功率找到一个解释，这一原理可能有助于提高 BACE-1 筛选中的命中率。
