Repurposing of drug candidates against Epstein-Barr virus: Virtual screening, docking computations, molecular dynamics, and quantum mechanical study

Abstract

Epstein-Barr virus (EBV) was the first tumor virus identified in humans, and it is mostly linked to lymphomas and cancers of epithelial cells. Nevertheless, there is no FDA-licensed drug feasible for this ubiquitous EBV viral contagion. EBNA1 (Epstein-Barr nuclear antigen 1) plays several roles in the replication and transcriptional of latent gene expression of the EBV, making it an attractive druggable target for the treatment of EBV-related malignancies. The present study targets EBV viral reactivation and upkeep by inhibiting EBNA1 utilizing a drug-repurposing strategy. To hunt novel EBNA1 inhibitors, a SuperDRUG2 database (> 4,600 pharmaceutical ingredients) was virtually screened utilizing docking computations. In accordance with the estimated docking scores, the most promising drug candidates then underwent MDS (molecular dynamics simulations). Besides, the MM-GBSA approach was applied to estimate the binding affinities between the identified drug candidates and EBNA1. On the basis of MM-GBSA//200 ns MDS, bezitramide (SD000308), glyburide (SD001170), glisentide (SD001159), and glimepiride (SD001156) unveiled greater binding affinities towards EBNA1 compared to KWG, a reference inhibitor, with ΔGbinding values of -44.3, -44.0, -41.7, -40.2, and -32.4 kcal/mol, respectively. Per-residue decomposition analysis demonstrated that LYS477, ASN519, and LYS586 significantly interacted with the identified drug candidates within the EBNA1 binding pocket. Post-dynamic analyses also demonstrated high constancy of the identified drug candidates in complex with EBNA1 throughout 200 ns MDS. Ultimately, electrostatic potential and frontier molecular orbitals analyses were performed to estimate the chemical reactivity of the identified EBNA1 inhibitors. Considering the current outcomes, this study would be an adequate linchpin for forthcoming research associated with the inhibition of EBNA1; however, experimental assays are required to inspect the efficiency of these candidates.

Fig 1. Schematic diagram of the utilized computational techniques for screening the SuperDRUG2 database against EBNA1.

Fig 2. 3D superimposition of the native structure (purple) and the anticipated docking pose (grey) of KWG against EBNA1.

Fig 3. 2D interaction diagram for (a) bezitramide (SD000308), (b) glyburide (SD001170), (c) glisentide (SD001159), (d) glimepiride (SD001156), and (e) KWG complexed with EBNA1.

Fig 4. Computed binding energies for the KWG and the top potent drug candidates bound with EBNA1 over 5 ns MDS in implicit and 10 ns, 25 ns, 100 ns, and 200 ns MDS in explicit water solvents.

Fig 5. (a) Binding affinity components and (b) 3D representation of the average structure of (i) bezitramide (SD000308), (ii) glyburide (SD001170), (iii) glisentide (SD001159), and (iv) glimepiride (SD001156) bound with EBNA1 over 200 ns MDS.

Fig 6. Illustration of per-residue energy decomposition analysis for bezitramide (SD000308)-, glyburide (SD001170)-, glisentide (SD001159)-, glimepiride (SD001156)-, and KWG-EBNA1 complexes over 200 ns MDS.

Fig 7. (a) Binding energy analysis, (b) CoM distance, and (c) RMSD of bezitramide (SD000308) (blue), glyburide (SD001170) (mauve), glisentide (SD001159) (green), glimepiride (SD001156) (dark yellow), and KWG (grey) towards EBNA1 throughout 200 ns MDS.

Fig 8. Number of H-bonds for (a) bezitramide (SD000308), (b) glyburide (SD001170), (c) glisentide (SD001159), (d) glimepiride (SD001156), and (e) KWG complexed with EBNA1 over 200 ns MDS.

Fig 9. (a) RMSF and (b) Rg of apo-EBNA1 (orange), bezitramide (SD000308)-EBNA1 (blue), glyburide (SD001170)-EBNA1 (mauve), glisentide (SD001159)-EBNA1 (green), glimepiride (SD001156)-EBNA1 (dark yellow), and KWG-EBNA1 (grey) over 200 ns MDS.

Fig 10. MEP maps of the final trajectory of (a) bezitramide (SD000308), (b) glyburide (SD001170), (c) glisentide (SD001159), (d) glimepiride (SD001156), and (e) KWG.

Fig 11. HOMO and LUMO plots of (a) bezitramide (SD000308), (b) glyburide (SD001170), (c) glisentide (SD001159), (d) glimepiride (SD001156), and (e) KWG.