Gianti Eleonora, Messick Troy E, Lieberman Paul M, Zauhar Randy J
Department of Chemistry and Biochemistry, University of the Sciences, 600 South, 43rd Street, Philadelphia, PA, 19104, USA.
Institute for Computational Molecular Science (ICMS), Temple University, SERC Building, 1925 North 12th Street, Philadelphia, PA, 19122, USA.
J Comput Aided Mol Des. 2016 Apr;30(4):285-303. doi: 10.1007/s10822-016-9899-y. Epub 2016 Apr 5.
The Epstein-Barr Nuclear Antigen 1 (EBNA1) is a critical protein encoded by the Epstein-Barr Virus (EBV). During latent infection, EBNA1 is essential for DNA replication and transcription initiation of viral and cellular genes and is necessary to immortalize primary B-lymphocytes. Nonetheless, the concept of EBNA1 as drug target is novel. Two EBNA1 crystal structures are publicly available and the first small-molecule EBNA1 inhibitors were recently discovered. However, no systematic studies have been reported on the structural details of EBNA1 "druggable" binding sites. We conducted computational identification and structural characterization of EBNA1 binding pockets, likely to accommodate ligand molecules (i.e. "druggable" binding sites). Then, we validated our predictions by docking against a set of compounds previously tested in vitro for EBNA1 inhibition (PubChem AID-2381). Finally, we supported assessments of pocket druggability by performing induced fit docking and molecular dynamics simulations paired with binding affinity predictions by Molecular Mechanics Generalized Born Surface Area calculations for a number of hits belonging to druggable binding sites. Our results establish EBNA1 as a target for drug discovery, and provide the computational evidence that active AID-2381 hits disrupt EBNA1:DNA binding upon interacting at individual sites. Lastly, structural properties of top scoring hits are proposed to support the rational design of the next generation of EBNA1 inhibitors.
爱泼斯坦-巴尔核抗原1（EBNA1）是由爱泼斯坦-巴尔病毒（EBV）编码的一种关键蛋白。在潜伏感染期间，EBNA1对于病毒和细胞基因的DNA复制及转录起始至关重要，并且是使原代B淋巴细胞永生化所必需的。尽管如此，将EBNA1作为药物靶点的概念还是新颖的。已有两个EBNA1晶体结构公开，并且最近发现了首个小分子EBNA1抑制剂。然而，尚未有关于EBNA1“可成药”结合位点结构细节的系统性研究报道。我们对EBNA1的结合口袋进行了计算识别和结构表征，这些口袋可能容纳配体分子（即“可成药”结合位点）。然后，我们通过与一组先前在体外测试过的用于抑制EBNA1的化合物（PubChem AID - 2381）进行对接来验证我们的预测。最后，我们通过进行诱导契合对接和分子动力学模拟，并结合通过分子力学广义玻恩表面积计算对属于可成药结合位点的多个命中物的结合亲和力预测，来支持对口袋可成药性的评估。我们的结果确立了EBNA1作为药物发现的靶点，并提供了计算证据，表明活性AID - 2381命中物在各个位点相互作用时会破坏EBNA1与DNA的结合。最后，提出了得分最高的命中物的结构特性，以支持下一代EBNA1抑制剂的合理设计。
