Epstein–Barr
virus (EBV), a known tumorigenic virus, is
associated with various neuropathies, including multiple sclerosis
(MS). However, there is no anti-EBV FDA-approved drug available in
the market. Our study targeted EBV protein EBV nuclear antigen 1 (EBNA1),
crucial in virus replication and expressed in all the stages of viral
latencies. This dimeric protein binds to an 18 bp palindromic DNA
sequence and initiates the process of viral replication. We chose
phytochemicals and FDA-approved MS drugs based on literature survey
followed by their evaluation efficacies as anti-EBNA1 molecules. Molecular
docking revealed FDA drugs ozanimod, siponimod, teriflunomide, and
phytochemicals; emodin; protoapigenone; and EGCG bound to EBNA1 with
high affinities. ADMET and Lipinski’s rule analysis of the
phytochemicals predicted favorable druggability. We supported our
assessments of pocket druggability with molecular dynamics simulations
and binding affinity predictions by the molecular mechanics generalized
Born surface area (MM/GBSA) method. Our results establish a stable
binding for siponimod and ozanimod with EBNA1 mainly via van der Waals
interactions. We identified hot spot residues like I481′, K477′,
L582′, and K586′ in the binding of ligands. In particular,
K477′ at the amino terminal of EBNA1 is known to establish
interaction with two bases at the major groove of the DNA. Siponimod
bound to EBNA1 engaging K477′, thus plausibly making it unavailable
for DNA interaction. Computational alanine scanning further supported
the significant roles of K477′, I481′, and K586′
in the binding of ligands with EBNA1. Conclusively, the compounds
showed promising results to be used against EBNA1.
Herpesviruses are ubiquitous viruses, specifically the Epstein Barr virus (EBV). EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) establish their latency for a long period in B-cells and their reactivation instigates dreadful diseases from cancer to neurological modalities. The envelope glycoprotein of these viruses makes an attachment with several host receptors. For instance; glycoprotein 350/220, gp42, gHgL and gB of EBV establish an attachment with CD21, HLA-DR, Ephs, and other receptor molecules to hijack the B- and epithelial cell machinery. Ephs are reported recently as potent receptors for EBV entry into epithelial cells. Eph receptors play a role in the maintenance and control of various cellular processes including morphology, adhesion, proliferation, survival and differentiation. Alterations in the structure and expression of Eph and ephrin (Eph ligands) molecules is entangled with various pathologies including tumours and neurological complications. Along with Eph, integrins, NRP, NMHC are also key players in viral infections as they are possibly involved in viral transmission, replication and persistence. Contrarily, KSHV gH is known to interact with EphA2 and -A4 molecules, whereas in the case of EBV only EphA2 receptors are being reported to date. The ELEFN region of KSHV gH was involved in the interaction with EphA2, however, the interacting region of EBV gH is elusive. Further, the gHgL of KSHV and EBV form a complex with the EphA2 ligand-binding domain (LBD). Primarily by using gL both KSHV and EBV gHgL bind to the peripheral regions of LBD. In addition to γ-herpesviruses, several other viruses like Nipah virus, Cedar virus, Hepatitis C virus and Rhesus macaque rhadinovirus (RRV) also access the host cells via Eph receptors. Therefore, we summarise the possible roles of Eph and ephrins in virus-mediated infection and these molecules could serve as potential therapeutic targets.
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