Piceid as a promising candidate for multi-target adjunctive therapeutic for inflammation-associated cervical cancer...

Cervical cancer remains a major global health challenge, as persistent high-risk human papillomavirus (HPV) infection along with chronic inflammation is one of the primary drivers that allows progression of cervical cancer. Despite recent advances in treatment strategies, there are still a lack of effective multi-target therapies that will modulate inflammatory, apoptotic and immune-regulatory pathways simultaneously. The originality of this study lies in conducting a comprehensive evaluation of piceid, as a multi-target immune-modulatory agent for cervical cancer focusing on molecular networks associated with inflammation. An integrated computational and experimental system was utilized to evaluate the potential therapeutic activity of piceid against molecular targets associated with cervical cancer. Molecular docking, MM-GBSA binding free energy calculations, molecular dynamics simulation for stability assessment of the complexes, ADMET profiling for estimating pharmacokinetic and toxic properties, and density functional theory (DFT) to assess electronic and chemical reactivity properties were all conducted in silico. In vitro validation of results was conducted using an MTT cell viability assay. Molecular docking revealed favorable binding of piceid to all five cervical cancer associated targets, with strongest affinity toward TGFBR2 (- 6.530 kcal/mol) and CASP8 (- 5.873 kcal/mol) which was further confirmed using MM-GBSA analysis. Molecular dynamics simulations (200 ns) demonstrated stable and flexible piceid-CASP8 and piceid-TGFBR2 complexes, with RMSD stabilization and minimal RMSF fluctuations in binding regions. Density functional theory analysis revealed favorable electronic properties supporting hydrogen bonding and electrostatic interactions. ADMET profiling predicted an overall favorable pharmacokinetic profile. Piceid exhibited dose-dependent cytotoxicity against HeLa cervical cancer cells, inducing marked morphological alterations, although with a higher IC₅₀ than doxorubicin. These findings suggest that piceid may serve as a promising candidate for multi-target immune-modulatory activity to prevent the progress of Cervical Cancer.