Exploring marine natural products for identifying putative candidates as EBNA1 inhibitors: An insight from molecular docking, molecular dynamics, and DFT computations

Abstract

Epstein-Barr virus (EBV), namely a DNA neoplasm virus, is liable for over 1 % of malignant neoplasms involving Hodgkin's and Burkitt's lymphoma as well as ventral cancer. Despite the crucial role of EBV in carcinoma evolution, no treatment has been discovered yet against EBV. Epstein-Barr nuclear antigen 1 (EBNA1), the EBV-encoded latent protein, is produced in all EBV-linked neoplasms and is the only latent protein in these cancer types. EBNA1 protein has multiple roles in the upkeep, reproduction, and EBV genome separation and can thus act as an attractive therapeutic target for treating EBV-related malignancies. In the past few decades, attempts have been made to develop specialized EBNA1 inhibitors to reduce EBNA1 expression or obstruct EBNA1-relied processes, but none has been approved yet. Marine natural products (MNPs) have garnered significant interest as potential sources of antiviral drug candidates. In seeking potent drug candidates to inhibit EBV reproduction, an MNP database containing >14,000 compounds was mined to hunt putative EBNA1 inhibitors using docking computations and molecular dynamics simulations (MDS). On the basis of binding energy (ΔG_binding) estimations over 200 ns MDS, UMHMNP351444649 and UMHMNP134128179 revealed a greater binding affinity towards EBNA1 compared to KWG, with ΔG_binding values of −35.6, −33.3, and −32.4 kcal/mol, respectively. Structural and energetical investigations of UMHMNP351444649 and UMHMNP134128179 complexed with EBNA1 were inspected, unveiling the great constancy of these inhibitors within the EBNA1 binding site. Moreover, the identified MNPs demonstrated favorable physicochemical and medicinal chemistry characteristics. Finally, density functional theory calculations were executed, and the results assured the outcomes obtained from docking computations and MDS. These findings proposed UMHMNP351444649 and UMHMNP134128179 as potential anti-EBV drug candidates that warrant further in-vitro and in-vivo assays.