title: An in silico appraisal of azoic and disulphide derivatives for anticancer activity against HPV E6 oncoprotein to medicate cervical cancer.
abstract: Cervical cancer is the second largest form of cancer to infest the leading cause of death in women worldwide. There are many causes of cancer but viruses are the most common among them. Human papillomaviruses (HPVs) are found to be the causative organism in almost 99.7% of the cases. HPV16 is the most frequent HPV type in malignant neoplastic growth in about 60% of cervical carcinoma cases. There is limited success achieved in surgical removal or by immune modulation and more effective therapies are under investigation. Observing the mortality rate we theorize a need for alternative treatment approaches and propose a blueprint of compounds with desirable properties that may lead to the development of drugs to treat HPV-associated neoplasias. E6 oncoprotein of HPV16 has a potential zinc finger domain critical for binding to E6AP, causing p53 degradation and malignancy. Some azoics and disulfides were selected depending on their affinity towards E6 zinc finger and thereby preventing E6-E6AP complex formation. Combinatorial nontoxic derivatives of these azoics and disulfides were docked and validated against the oncoprotein to inhibit E6-E6AP interaction. Among these, two compounds (E)-N-(2-amino-2-oxoethyl)-N-(4-chlorophenyl) diazene-1,2-dicarboxamide and (E)-N-(2- amino-2-methylpropyl)-N-(thiophen-2-yl)diazene-1,2-dicarboxamide showed binding affinity of -23.70, -19.53 and -5.49, -4.65 Kcal/mol respectively in FlexX and Autodock4.2. These compounds are found more effective than those of the approved E6-E6AP binding inhibitors. Pharmacophores of these compounds were generated to confirm it with pharm mapping mechanism. The study may confer the way of design of new mechanism and new compounds to treat cervical cancer.
authors.forename: Arpita Das
authors.initials: AD
authors.lastname: Choudhury
authors.forename: Manabendra Dutta
authors.initials: MD
authors.lastname: Choudhury
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chetia
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Bioinformatics Centre, Assam University, Silchar, 788011, India. arpitadaschoudhury@gmail.com.
authors.forename: Anupam Das
authors.initials: AD
authors.lastname: Talukdar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001391:Azo Compounds / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D005260:Female; D052162:Human papillomavirus 16 / Q000737:chemistry; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000737:chemistry; D030361:Papillomavirus Infections / Q000188:drug therapy; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012107:Research Design; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D016335:Zinc Fingers
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D004220:Disulfides; C068651:E6 protein, Human papillomavirus type 16; D008024:Ligands; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C004525:azodicarbonamide; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases