title: Computational analysis of EBNA1 "druggability" suggests novel insights for Epstein-Barr virus inhibitor design.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences, 600 South, 43rd Street, Philadelphia, PA, 19104, USA. eleonora.gianti@gmail.com.|Institute for Computational Molecular Science (ICMS), Temple University, SERC Building, 1925 North 12th Street, Philadelphia, PA, 19122, USA. eleonora.gianti@gmail.com.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gianti
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Troy E
authors.initials: TE
authors.lastname: Messick
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences, 600 South, 43rd Street, Philadelphia, PA, 19104, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Zauhar
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000821:virology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000187:drug effects; D055808:Drug Discovery; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry* / Q000627:therapeutic use; D004854:Herpesvirus 4, Human / Q000737:chemistry / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D008024:Ligands; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D008024:Ligands
keywords: Computational approaches to pocket finding; EBNA1 “druggability” assessment; Molecular docking; Structure-based drug design