Exploitation of Biocomputational Approaches for siRNA ‐Mediated Gene Silencing of HPV : A Novel Therapeutic Strategy for Cervical Cancer

ABSTRACT Background With recurrent high‐risk human papillomavirus (HPV) infections, especially HPV16 and HPV18, cervical cancer is the fourth most common disease among women. The functional alterations of the E6 and E7 proteins are essential to the oncogenic process of high‐risk HPVs and cervical cancer development. Aims The objective of this research is to design highly targeted and efficient small interfering RNAs (siRNAs) that target both HPV16 and HPV18, employing cutting‐edge computational approaches to enhance therapeutic potential through a systematic bioinformatics‐driven approach. Methods and Results This study utilized the i‐Score Designer to identify and evaluate four potential small interfering RNAs (siRNAs) (E6_69, E6_451, E7_66, and E7_193) based on various algorithm criteria, including Ui‐Tei, Amarzguioui, i‐Score, and Reynolds scores. Consequently, a docking analysis was conducted to elucidate the intermolecular interactions between the RNA‐induced silencing complex (RISC) proteins and the designed siRNAs. All siRNAs passed the recommended cutoff values, indicating a strong potential for gene silencing. Thermodynamic and structural analyses revealed that the designed siRNAs had favrable melting temperatures and free energies, suggesting adequate stability for effective gene silencing. Further, docking analysis demonstrated significant binding affinities and interaction profiles with the major RISC proteins (Dicer, Ago2, TRBP). The E6_69 and E7_193 significantly showed strong binding and intermolecular interactions, especially with Ago2, highlighting the potential for HPV gene silencing. Conclusion The study revealed the potential of the designed siRNAs in silencing the E6 and E7 genes and their therapeutic applications against HPV. Future research should focus on validating these findings across various experiments, both in vivo and in vitro, and exploring alternative delivery approaches to enhance therapeutic efficacy.