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

in PloS one by Mahmoud A A Ibrahim, Alaa M A Hassan, Eslam A R Mohamed, Gamal A H Mekhemer, Peter A Sidhom, Mohamed A El-Tayeb, Shahzeb Khan, Tamer Shoeib, Mahmoud E S Soliman, Alaa H M Abdelrahman

TLDR

  • The study aims to find new drugs to treat a virus called EBV, which is linked to many types of cancer. The researchers used a computer program to find potential drugs that might work by blocking a protein called EBNA1, which helps the virus replicate. The researchers then used a computer program to test how well these drugs might work by simulating how they would interact with EBNA1. The study found that four drugs, bezitramide, glyburide, glisentide, and glimepiride, had the strongest interactions with EBNA1. These drugs could potentially be used to treat EBV-related cancers, but more research is needed to see if they work well in people.

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.

Overview

  • The study aims to identify novel EBNA1 inhibitors using a drug-repurposing strategy. The researchers used a SuperDRUG2 database and docking computations to screen for potential drug candidates. Molecular dynamics simulations (MDS) and molecular mechanics-generalized Born surface area (MM-GBSA) were used to estimate the binding affinities of the identified drug candidates. The study found that bezitramide, glyburide, glisentide, and glimepiride had greater binding affinities towards EBNA1 compared to 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. Electrostatic potential and frontier molecular orbitals analyses were performed to estimate the chemical reactivity of the identified EBNA1 inhibitors.

Comparative Analysis & Findings

  • The study found that bezitramide, glyburide, glisentide, and glimepiride had greater binding affinities towards EBNA1 compared to 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. Electrostatic potential and frontier molecular orbitals analyses were performed to estimate the chemical reactivity of the identified EBNA1 inhibitors.

Implications and Future Directions

  • The study's findings suggest that bezitramide, glyburide, glisentide, and glimepiride could be potential EBNA1 inhibitors for the treatment of EBV-related malignancies. However, experimental assays are required to inspect the efficiency of these candidates. Future research could focus on the development of more potent and selective EBNA1 inhibitors, as well as the exploration of the potential side effects and toxicity of these drugs. Additionally, the study's findings could be used to inform the design of clinical trials for the treatment of EBV-related malignancies.
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