Computational analysis of lupenone derivatives as potential inhibitor of human papillomavirus oncoprotein E6 associated cervical cancer.

Cervical cancer remains a major global health challenge, largely driven by persistent infections with high-risk human papillomavirus (HPV). Although preventive vaccines have reduced cervical cancer incidence in some settings, effective therapeutic strategies for established HPV-associated malignancies remain limited. High-risk HPV types (particularly 16 and 18) utilize their E6 oncoprotein to promote ubiquitin-mediated degradation of the tumor suppressor p53, thereby facilitating uncontrolled cell proliferation and immune evasion. Targeting E6 has thus emerged as a key strategy to counteract HPV-driven carcinogenesis. In this work, we employed a comprehensive in silico framework-encompassing density functional theory (DFT), ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, molecular docking (including refinement and validation), and molecular dynamics (MD) simulations-to evaluate a series of chemically modified lupenone derivatives as potential HPV oncoprotein inhibitors. Initially, lupenone was modified with different functional groups, and each derivative was screened for drug-likeness via ADMET analysis to confirm pharmacological viability. Concurrently, pharmacophore mapping highlighted key alignments between ligand functional groups and pharmacophoric sites, while DFT calculations elucidated each compound's electronic structure, conformational stability, and chemical reactivity. Subsequent docking assessments against E6 oncoprotein and molecular dynamics simulations further confirmed structural robustness in several top-performing compounds, indicating minimal conformational fluctuations over time. These findings demonstrate the potential of lupenone derivatives as promising scaffolds for anti-HPV therapy. However, in vitro and in vivo investigations are necessary to confirm their efficacy, toxicity profiles, and clinical relevance in mitigating HPV-related cervical cancer.