Structure-Guided Discovery of Drug-like Compounds Targeting HPV16 E6 for Antiviral Therapy Development.

Background: Human papillomavirus type 16 (HPV16) E6 oncoprotein is a key factor in the progression of cervical and other HPV-related cancers. Targeting E6 with small molecule inhibitors represents a promising strategy for the development of novel antiviral therapies. Objectives: This study aimed to discover and characterize small-molecule compounds that exhibit high affinity for HPV16 E6, possess favorable drug-like properties, and inhibit HPV16 E6, using advanced computational approaches. Materials and Methods: We integrated molecular dynamics simulations to capture the conformational flexibility of HPV16 E6 and employed structure-based virtual screening to identify potential inhibitors from a large chemical library. The binding stability and interaction patterns of selected compounds were evaluated through molecular docking, binding free energy calculations, and extended molecular dynamics simulations. In silico ADMET profiling was performed to assess the pharmacokinetic and toxicity properties of the top candidates. Results: Nine lead compounds demonstrated stable binding to a key functional residue (CYS51) of HPV16 E6, with strong theoretical binding affinities confirmed by MM-GBSA calculations and molecular dynamics analysis. ADMET predictions indicated that most candidates possessed favorable pharmacokinetic profiles, although two compounds showed potential toxicity concerns. Conclusion: Our findings provide a robust computational framework for the identification of drug-like small molecules targeting HPV16 E6, offering promising candidates for further development as antiviral agents against HPV-associated diseases. Experimental validation is warranted to confirm the inhibitory activity and therapeutic potential of these compounds.