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.

Development of New Inhibitors of HDAC1–3 Enzymes Aided by In Silico Design Strategies

“…The FlexX docking algorithm as implemented in LeadIT executed the docking of all selected virtual compounds in the library. FlexX is based on breaking ligands into fragments at rotatable bonds and then building them up again fragment by fragment and scoring the solutions. − The output was limited to a maximum of top 10 poses per ligand; subsequently, we computed a free binding energy assessment (ΔG) in kcal/mol of the protein–ligand complex and its ligand efficiency using Hyde. , …”

In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

“…Some of these residues are found to be conserved among HPV6, HPV11, HPV16, and HPV18 zinc fingers. This demonstrates the possibility of the zinc finger domain to be a drug target [ 41 ].…”

Virus proteins similar to human proteins as possible disturbance on human pathways

“…Moreover, a study showed that the EBV protein called latent infection membrane protein 1 (LMP1) can act as a constitutively active receptor that mimics activated CD40, which is a member of the tumor necrosis factor receptor family (Mosialos et al 1995). Also there is another research indicated the E6 oncoprotein of HPV16 has a potential zinc finger domain critical for binding to E6AP ubiquitin-protein ligase which is an enzyme involved in targeting proteins for degradation within human cells, causing p53 degradation and malignancy (Choudhury et al 2014).…”