Comparative modeling and docking studies of p16ink4/Cyclin D1/Rb pathway genes in lung cancer revealed functionally interactive residue of RB1 and its functional partner E2F1

• Main Authors: e Zahra Syeda Naqsh, Khattak Naureen Aslam, Mir Asif
• Format: Article
• Language: English
• Published: BMC 2013-01-01
• Series: Theoretical Biology and Medical Modelling
• Online Access: http://www.tbiomed.com/content/10/1/1

<p>Abstract</p> <p>Background</p> <p>Lung cancer is the major cause of mortality worldwide. Major signalling pathways that could play significant role in lung cancer therapy include (1) Growth promoting pathways (Epidermal Growth Factor Receptor/Ras/ PhosphatidylInositol 3-Kinase) (2) Growth inhibitory pathways (<it>p53/Rb/P14ARF, STK11</it>) (3) Apoptotic pathways (<it>Bcl-2/Bax/Fas/FasL</it>). <it>Insilico</it> strategy was implemented to solve the mystery behind selected lung cancer pathway by applying comparative modeling and molecular docking studies.</p> <p>Results</p> <p>YASARA [v 12.4.1] was utilized to predict structural models of <it>P16-INK4</it> and <it>RB1</it> genes using template 4ELJ-A and 1MX6-B respectively. WHAT CHECK evaluation tool demonstrated overall quality of predicted P16-INK4 and RB1 with Z-score of −0.132 and −0.007 respectively which showed a strong indication of reliable structure prediction. Protein-protein interactions were explored by utilizing STRING server, illustrated that <it>CDK4</it> and <it>E2F1</it> showed strong interaction with <it>P16-INK4</it> and <it>RB1</it> based on confidence score of 0.999 and 0.999 respectively. In order to facilitate a comprehensive understanding of the complex interactions between candidate genes with their functional interactors, GRAMM-X server was used. Protein-protein docking investigation of <it>P16-INK4</it> revealed four ionic bonds illustrating Arg47, Arg80,Cys72 and Met1 residues as actively participating in interactions with <it>CDK4</it> while docking results of <it>RB1</it> showed four hydrogen bonds involving Glu864, Ser567, Asp36 and Arg861 residues which interact strongly with its respective functional interactor <it>E2F1</it>.</p> <p>Conclusion</p> <p>This research may provide a basis for understanding biological insights of <it>P16-INK4</it> and <it>RB1</it> proteins which will be helpful in future to design a suitable drug to inhibit the disease pathogenesis as we have determined the interacting amino acids which can be targeted in order to design a ligand <it>in-vitro</it> to propose a drug for clinical trials. Protein -protein docking of candidate genes and their important interacting residues likely to be provide a gateway for developing computer aided drug designing.</p>