Identification of E6 Inhibitors Employing Energetically Optimized Structure‐Based Pharmacophore Modelling, Ligand Docking and Molecular Dynamics Simulations Studies

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AbstractHigh‐risk HPV DNA has been found in nearly all cases of cervical cancer (CC). The viral E6 protein in association with E6AP (E6 binding protein) leads to degradation of apoptotic p53 protein. So, inhibition of E6 can be a promising target for HPV associated CC. In this work, protein‐protein alignment and protein interaction analysis were done to identify the amino acid residues undergoing conformational changes when E6‐E6AP complex recruited p53 protein. Then ‘SiteMap’ of Maestro was used to define a possible binding pocket. An e‐pharmacophore model (ADHRRN) was built based on the receptor cavity and screened against four different focussed libraries of 27,354 compounds. The hits were further analysed using docking, MM‐GBSA analysis and molecular dynamics simulations study. Eight hits have been reported here, but compound 7 also known as Diospyrin was identified as the best hit. It showed possible H‐bond interaction with TYR32, CYS51, SER74 and ARG131 amino acid residues.