Drug repurposing approach for the identification and designing of potential E6 inhibitors against cervical cancer: an in silico investigation

Abstract

Repurposing of ‘old’ drugs to treat both common and rare diseases has garnered huge attention of the researchers because of the high attrition rates and extortionate cost involved in new drug discovery. Almost in 100% of cases, high-risk HPV DNA has been found to be associated with cervical cancer. The viral E6 and E7 genes are regularly maintained and expressed in cervical cancer. So, the functional inhibition of E6 can be a promising therapeutic target for HPV-associated cervical cancer. In the present study, a five feature (AADRR) e-pharmacophore model was built based on amino acid residues reported by Zanier et al. and predicted by the Sitemap module of Maestro (Schrodinger). FDA-approved drugs library was screened employing the developed model and identified hits (based on phase screen score) were further put for docking and molecular dynamics (MD) simulations studies. The top two identified hits were ZINC000001543916 (valganciclovir; anti-viral drug) and ZINC000003795098 (cytarabine; anti-cancer drug). Incidentally, our target protein E6 can be classified under the field of tumour virology. Identified five hits are either purine or pyrimidine derivatives. We have also reported compound ASK4, a valganciclovir derivative as a potential E6 inhibitor. Molecular docking studies suggest that H-bond interaction with TYR32 and CYS51 amino acid residues is important for E6 inhibition. MD simulations studies indicated that the ligands might form stable complex with the E6 protein. All the designed compounds showed acceptable ADME profile. Further purine and pyrimidine scaffold can be used to design novel E6 inhibitors.