Structure-Based Identification and Dynamic Profiling of Mitragyna speciosa Metabolites Targeting HPV E6 and EBNA1 in Cervical Cancer

Abstract

Cervical cancer remains the fourth most commonly diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Persistent infection with high-risk human papillomaviruses (HPVs), particularly types 16 and 18, is recognized as the primary etiological factor. Moreover, accumulating evidence suggests that co-infection with Epstein–Barr virus (EBV) may exacerbate cervical cancer progression, likely through the synergistic disruption of host cellular control mechanisms. The viral oncoproteins HPV E6 and Epstein–Barr nuclear antigen 1 (EBNA1) play pivotal roles in carcinogenesis by inactivating tumor suppressor pathways and maintaining viral genomes within host cells. Consequently, these proteins represent attractive molecular targets for the development of antiviral therapeutics aimed at virus-driven malignancies. In this study, a structure-based virtual screening approach was employed to evaluate 50 phytometabolites derived from Mitragyna speciosa against three key viral targets: HPV16 E6 (PDB ID: 6SJV) and two crystal structures of EBNA1 (PDB IDs; 6VH6 and 6NPP), respectively. Molecular docking using AutoDock Vina via AutoDock Tools facilitated the identification of the top five ligands with the most favorable binding affinities. These were further subjected to detailed interaction analysis, in silico pharmacokinetic assessment using SwissADME, and oral toxicity prediction via the ProTox-II platform. Among the shortlisted compounds, β-Stigmasterol and oleanolic acid emerged as the most promising candidates based on their superior binding energies, favorable ADME profiles, and acceptable predicted safety margins. Collectively, these findings support the therapeutic potential of selected Mitragyna speciosa metabolites as dual-target inhibitors of EBV and HPV oncoproteins, offering a valuable framework for future antiviral drug development.