通过计算机筛选和结合模拟鉴定一类新型的BRD4抑制剂,ACS Omega

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通过计算机筛选和结合模拟鉴定一类新型的BRD4抑制剂
ACS Omega ( IF 3.7 ) Pub Date : 2017-08-21 00:00:00 , DOI: 10.1021/acsomega.7b00553
Bryce K. Allen , Saurabh Mehta ₁ , Stuart W. J. Ember ₂ , Jin-Yi Zhu ₂ , Ernst Schönbrunn ₂ , Nagi G. Ayad , Stephan C. Schürer

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计算筛选是一种根据配体和靶标信息建立的结构和生化属性对小分子化合物进行优先排序的方法。以前，我们已经开发了可扩展的虚拟筛选工作流程，以识别新型的多靶激酶/溴结构域抑制剂。在本研究中，我们确定了几种新颖的N-[3-（2-氧代-吡咯烷基）苯基]-苯磺酰胺衍生物在我们的整体对接方案中得分很高。我们通过生物化学方法对这些化合物对BRD4（BD1）的结合亲和力进行了定量，并生成了共晶体结构，并将其沉积在蛋白质数据库中。由于在虚拟筛选管线中获得的对接位姿与实验共晶体结构不符，我们通过进行分子动力学（MD）模拟评估了其精确结合模式的预测。MD模拟紧密地再现了所有化合物在实验中观察到的蛋白质－配体共晶结合构象和相互作用。这些结果表明，计算工作流程可生成实验质量的蛋白质-配体结合模型，

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Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations

Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein–ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein–ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors.

更新日期：2017-08-21

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