Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets,Journal of Chemical Information and Modeling

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Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-02-26 00:00:00 , DOI: 10.1021/acs.jcim.7b00733
Joana Magalhães ₁ , Giannamaria Annunziato ₁ , Nina Franko ₂ , Marco Pieroni ₁ , Barbara Campanini ₂ , Agostino Bruno _{1,

3} , Gabriele Costantino ₁

Affiliation

Saturation transfer difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small-molecule optimization processes. However, STD does not provide any structural details about the ligand–target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the characterization of ligand–target complexes that are instrumental for drug design purposes. As an example, we have studied the interaction between StOASS-A, a potential antibacterial target, and an inhibitor previously reported. This approach allowed us to consider the ligand–target complex from a dynamic point of view, revealing the presence of an accessory subpocket which can be exploited to design novel StOASS-A inhibitors. As a proof of concept, a small library of derivatives was designed and evaluated in vitro, displaying the expected activity.

中文翻译：

增强采样方法与饱和转移差异实验的集成，可识别可药用蛋白质的口袋

饱和转移差异（STD）是常规用于药物发现的NMR技术，用于鉴定与结合蛋白腔相关的配体部分。这对于在小分子优化过程中指导药物化学工作非常重要。但是，STD没有提供有关正在研究的配体-靶标复合物的任何结构细节。本文中，我们报告了一种新的集成方法的应用，该方法将增强的采样方法与STD实验相结合，用于表征对药物设计有用的配体-目标复合物。例如，我们研究了St之间的相互作用OASS-A，一种潜在的抗菌靶标，也是先前报道的一种抑制剂。这种方法使我们能够从动态的角度考虑配体-靶标复合物，揭示了辅助亚口袋的存在，该亚口袋可用于设计新型St OASS-A抑制剂。作为概念验证，在体外设计并评估了一个小的衍生物库，显示了预期的活性。

更新日期：2018-02-26

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