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Published on: July 15, 2019
Repurposing of drug candidates against Epstein-Barr virus: Virtual screening, docking computations, molecular
Mahmoud A A Ibrahim1,2, Alaa M A Hassan1, Eslam A R Mohamed1
1Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt.
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.
Insights
This study identified potential new drugs to inhibit Epstein-Barr nuclear antigen 1 (EBNA1), a key target for treating EBV-related cancers. Promising candidates like bezitramide and glyburide show strong binding affinity, paving the way for further research.
Area of Science:
- Oncology
- Virology
- Computational Chemistry
Background:
- Epstein-Barr virus (EBV) is linked to human lymphomas and epithelial cancers.
- No FDA-approved drugs exist for EBV infections.
- EBNA1 is crucial for EBV replication and gene expression, making it a druggable target.
Purpose of the Study:
- To identify novel EBNA1 inhibitors using a drug-repurposing strategy.
- To target EBV reactivation and maintenance by inhibiting EBNA1.
Main Methods:
- Virtual screening of the SuperDRUG2 database (>4,600 compounds) using docking.
- Molecular dynamics simulations (MDS) and MM-GBSA for binding affinity estimation.
- Per-residue decomposition, post-dynamic, and molecular orbital analyses.
Main Results:
- Bezitramide, glyburide, glisentide, and glimepiride showed high binding affinities to EBNA1.
- These candidates exhibited greater binding than the reference inhibitor KWG.
- Specific residues (LYS477, ASN519, LYS586) were key interaction points within the EBNA1 binding pocket.
Conclusions:
- The identified drug candidates demonstrate significant potential for inhibiting EBNA1.
- These findings provide a foundation for future experimental studies on EBV-targeted therapies.
- Further experimental validation is necessary to confirm the efficacy of these potential EBNA1 inhibitors.
