title: Virtual Screening for Potential Inhibitors of High-Risk Human Papillomavirus 16 E6 Protein.
abstract: Human papillomavirus (HPV), a life-threatening infection, is the leading cause of cancer mortality among women worldwide and needs for designing anticancerous drugs. In the present study, we explored specific novel inhibitors against E6 oncoprotein of high-risk HPV 16, known to inactivate tumor suppressor p53 protein. A homology model of HPV 16 E6 was built and validated using bioinformatics approach. A total of 5000 drug-like compounds were downloaded from ZINC database based on the properties similar to the known inhibitor Jaceosidin (5,7-dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-6-methoxy-4H-chromen-4-one). Virtual-ligand-screening approaches were applied to screen appropriate drug-like compounds using molecular docking program AutoDock Vina in PyRx 0.8, and five best novel drug-like compounds were identified as potential competitive inhibitors against HPV 16 E6 compared to Jaceosidin. Two among these five identified most potential inhibitors, N-[(5-methyl-1H-benzimidazol-2-yl)methyl]-4-oxo-3,4-dihydrophthalazine-1-carboxamide and 6-[3-(3-fluoro-4-methyl-phenyl)-1,2,4-oxadiazol-5-yl]-1,4-dihydroquinoxaline-2,3-dione, were found to interact with E6 with binding energy of [Formula: see text] and [Formula: see text] kcal/mol, respectively, and form H-bonds with p53 binding site of E6 protein residues 113-122 (CQKPLCPEEK). These two inhibitors may help restoration of p53 functioning. The bioinformatics approach extends a promising platform for developing anticancerous competitive inhibitors targeting high-risk HPV 16.
authors.affiliation: Biochemistry and Bioinformatics Centre, Mahatma Gandhi Institute of Medical Sciences, Sevagram, India, satishangral@gmail.com.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.forename: Lingaraja
authors.initials: L
authors.lastname: Jena
authors.forename: Kanchan
authors.initials: K
authors.lastname: Mohod
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Daf
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Varma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D052162:Human papillomavirus 16 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000821:virology; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; C068651:E6 protein, Human papillomavirus type 16; D008024:Ligands; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins