Homology Modeling, Virtual Screening, Prime-MMGBSA, AutoDock-Identification of Inhibitors of FGR Protein
Narasimha Muddagoni, Revanth Bathula, Mahender Dasari, Sarita Rajender Potlapally, Z Momenimovahed, A Tiznobaik, S Taheri, H Salehiniya, G Berton, L Fumagalli, C Laudanna, C Sorio, H.-S Kim, H Han, G Armaiz-Pena, R Stone, E Nam, J.-W Lee, M Shahzad, A Nick, S Lee, J.-W Roh, M Nishimura, L Mangala, J Bottsford-Miller, G Gallick, G Lopez-Berestein, A Sood, K Siveen, K Prabhu, I Achkar, S Kuttikrishnan, S Shyam, A Khan, M Merhi, S Dermime, S Uddin, T Erpel, S Courtneidge, S Huveneers, E Danen, A Fiser, M Bhargavi, N Vhora, G Lanka, G Somadi, S Kanth, A Jain, S Potlapally, S Macgowan, F Madeira, T Britto-Borges, M Warowny, A Drozdetskiy, J Procter, G Barton, S Dong, J Sun, Z Mao, L Wang, Y.-L Lu, J Li, M Bhargavi, S Sivan, S Potlapally, J Phillips, R Braun, W Wang, J Gumbart, E Tajkhorshid, E Villa, C Chipot, R Skeel, L Kal, K Schulten, P Sneha, D Kumar, S Saini, K Kajal, R Magesh, R Siva, C George Priya Doss, M Wiederstein, M Sippl, R Laskowski, J Rullmann, M Macarthur, R Kaptein, J Thornton, N Salam, R Nuti, W Sherman, Y Dizdaroglu, C Albay, T Arslan, A Ece, E Turkoglu, A Efe, M Senturk, C Supuran
Abstract
Carcinogenesis is a multi-stage process in which damage to a cell's genetic material changes the cell from normal to malignant. Tyrosine-protein kinase FGR is a protein, member of the Src family kinases (SFks), nonreceptor tyrosine kinases involved in regulating various signaling pathways that promote cell proliferation and migration. FGR protein is also called Gardner-Rasheed Feline Sarcoma viral (v-fgr) oncogene homolog. FGR, FGR protein has an aberrant expression upregulated and activated by the tumor necrosis factor activation (TNF), enhancing the activity of FGR by phosphorylation and activation, causing ovarian cancer. In the present study, 3D structure of FGR protein is built by using comparative homology modeling techniques using MODELLER9.9 program. Energy minimization of protein is done by NAMD-VMD software. The quality of the protein is evaluated with ProSA, Verify 3D and Ramchandran Plot validated tools. The active site of protein is generated using SiteMap and literature Studies. In the present study of research, FGR protein was subjected to virtual screening with TOSLab ligand molecules database in the Schrodinger suite, to result in 12 lead molecules prioritized based on docking score, binding free energy and ADME properties. These lead molecules are considered as a new policy against ovarian cancer.