Ligand Strain Energy in Large Library Docking,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Ligand Strain Energy in Large Library Docking
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-09-01 , DOI: 10.1021/acs.jcim.1c00368
Shuo Gu ₁ , Matthew S Smith _{1,

2} , Ying Yang ₁ , John J Irwin ₁ , Brian K Shoichet ₁

Affiliation

While small molecule internal strain is crucial to molecular docking, using it in evaluating ligand scores has remained elusive. Here, we investigate a technique that calculates strain using relative torsional populations in the Cambridge Structural Database, enabling fast precalculation of these energies. In retrospective studies of large docking screens of the dopamine D4 receptor and of AmpC β-lactamase, where close to 600 docking hits were tested experimentally, including such strain energies improved hit rates by preferentially reducing the ranks of strained high-scoring decoy molecules. In a 40-target subset of the DUD-E benchmark, we found two thresholds that usefully distinguished between ligands and decoys: one based on the total strain energy of the small molecules and another based on the maximum strain allowed for any given torsion within them. Using these criteria, about 75% of the benchmark targets had improved enrichment after strain filtering. Relying on precalculated population distributions, this approach is rapid, taking less than 0.04 s to evaluate a conformation on a standard core, making it pragmatic for precalculating strain in even ultralarge libraries. Since it is scoring function agnostic, it may be useful to multiple docking approaches; it is openly available at http://tldr.docking.org.

中文翻译：

大型库对接中的配体应变能

虽然小分子内部应变对分子对接至关重要，但在评估配体分数时使用它仍然难以捉摸。在这里，我们研究了一种使用剑桥结构数据库中的相对扭转种群计算应变的技术，从而能够快速预先计算这些能量。在对多巴胺 D4 受体和 AmpC β-内酰胺酶的大型对接筛选的回顾性研究中，实验测试了近 600 个对接命中，包括这种应变能量通过优先降低应变的高得分诱饵分子的等级来提高命中率。在 DUD-E 基准的 40 个目标子集中，我们发现了两个有用区分配体和诱饵的阈值：一种基于小分子的总应变能，另一种基于其中任何给定扭转允许的最大应变。使用这些标准，大约 75% 的基准目标在应变过滤后提高了富集度。依靠预先计算的种群分布，这种方法速度很快，只需不到 0.04 秒即可评估标准核心上的构象，即使在超大型文库中也可用于预先计算应变。由于它与评分功能无关，因此可能对多种对接方法有用；它可在 http://tldr.docking.org 上公开获得。04 秒评估标准核心上的构象，使其适用于在超大型库中预先计算应变。由于它与评分功能无关，因此可能对多种对接方法有用；它可在 http://tldr.docking.org 上公开获得。04 秒评估标准核心上的构象，使其适用于在超大型库中预先计算应变。由于它与评分功能无关，因此可能对多种对接方法有用；它可在 http://tldr.docking.org 上公开获得。

更新日期：2021-09-27

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11