title: Tumor necrosis factor receptor superfamily 10B (TNFRSF10B): an insight from structure modeling to virtual screening for designing drug against head and neck cancer.
abstract: BACKGROUND
  Head and neck cancer (HNC) belongs to a group of heterogeneous disease with distinct patterns of behavior and presentation. TNFRSF10B, a tumor suppressor gene mapped on chromosome 8. Mutation in candidate gene is responsible for the loss of chromosome p arm which is frequently observed in head and neck tumors. TNFRSF10B inhibits tumor formation through apoptosis but deregulation encourages metastasis, migration and invasion of tumor cell tissues.
  
  
  RESULTS
  Structural modeling was performed by employing MODELLER (9v10). A suitable template [2ZB9] was retrieved from protein databank with query coverage and sequence identity of 84% and 30% respectively. Predicted Model evaluation form Rampage revealed 93.2% residues in favoured region, 5.7% in allowed region while only 1 residue is in outlier region. ERRAT and ProSA demonstrated 51.85% overall quality with a -1.08 Z-score of predicted model. Molecular Evolutionary Genetics Analysis (MEGA 5) tool was executed to infer an evolutionary history of TNFRSF10B candidate gene. Orthologs and paralogs [TNFRSF10A & TNFRSF10D] protein sequences of TNFRSF10B gene were retrieved for developed ancestral relationship. Topology of tree presenting TNFRSF10A gene considered as outgroup. Human and gorilla shared more than 90% similarities with conserved amino acid sequence. Virtual screening approach was appliedfor identification of novel inhibitors. Library (Mcule) was screened for novel inhibitors and utilized the scrutinized lead compounds for protein ligand docking. Screened lead compounds were further investigated for molecular docking studies. STRING server was employed to explore protein-protein interactions of TNFRSF10B target protein. TNFSF10 protein showed highest 0.999 confidence score and selected protein-protein docking by utilizing GRAMM-X server. In-silico docking results revealed I-58, S-90 and A-62 as most active interacting residues of TNFRSF10B receptor protein with R-130, S-156 and R-130 of TNFSF10B ligand protein.
  
  
  CONCLUSIONS
  Current research may provide a backbone for understanding structural and functional insights of TNFRSF10B protein. The designed novel inhibitors and predicted interactions might serve to inhibit the disease. Effective in-vitro potent ligands are required which will be helpful in future to design a drug to against Head and neck cancer disease. There is an urgent need for affective drug designing of head and neck cancer and computational tools for examining candidate genes more efficiently and accurately are required.
authors.affiliation: Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan.
authors.forename: Rana Adnan
authors.initials: RA
authors.lastname: Tahir
authors.forename: Sheikh Arslan
authors.initials: SA
authors.lastname: Sehgal
authors.forename: Naureen Aslam
authors.initials: NA
authors.lastname: Khattak
authors.forename: Jabar Zaman
authors.initials: JZ
authors.lastname: Khan Khattak
authors.forename: Asif
authors.initials: A
authors.lastname: Mir
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015195:Drug Design; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008958:Models, Molecular; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human