C-۷۱۹۸۰۲۶۲, A novel small molecule against human papilloma virus-۱۶ E۶ (HPV-۱۶ E۶) with anticancer potency against cervical cancer: A computational guided in vitro approach

Objective(s): Human papillomavirus-۱۶ E۶ (HPV-۱۶ E۶) forms a heterodimer complex to up-regulate the degradation of tumor suppressor protein p۵۳ to promote cervical cancer. This study aims to identify a novel small molecule against E۶ with anticancer efficacy against HPV-۱۶, a prime high-risk serotype inducer for cervical cancer.Materials and Methods: Autodock-vina-based high-throughput virtual screening and atomistic molecular dynamic simulations were used for identification of targeted lead molecules. HPV-۱۶ infected SiHa and CaSki cell lines were used to validate the lead compound in vitro. Proliferation of cancer cells was analyzed by MTT assay and flow cytometry was used to analyze target inhibition, apoptosis, and p۵۳.  Results: High throughput virtual screening and molecular dynamic simulation identified C-۷۱۹۸۰۲۶۲ as a lead candidate that could bind HPV-E۶. Atomistic molecular dynamic simulation of E۶ bound C-۷۱۹۸۰۲۶۲ for ۲۰۰ ns showed that the predicted ligand binding was stable with minimal energy expenditure, proposing the viability and veracity of the assessed molecule. C-۷۱۹۸۰۲۶۲ inhibited the proliferation of SiHa and CaSki cells with GI۵۰ values of ۳۵۵.۷۰ nM and ۵۰۵.۹۰ nM, respectively. The compound reduced HPV-۱۶ E۶ while inducing early and late-phase apoptosis in these cells. Treatment with C-۷۱۹۸۰۲۶۲ increased the p۵۳-positive populations in SiHa and CaSki cells.  Conclusion: C-۷۱۹۸۰۲۶۲ was identified as a novel lead molecule that could inhibit the HPV-۱۶ E۶ and increase p۵۳ in cervical cancer cells. Further in vitro and in vivo validation is warranted to consolidate and corroborate this lead compound against HPV-induced cancer progression.

کلیدواژه ها:

Apoptosis ، Cervical Cancer ، E۶ High-throughput virtual- screening ، HPV ، Molecular dynamic-simulations ، P۵۳