Molecular Docking Studies of 5-Amino Pyrazole Derivatives Against Protein Kinases as Drug Targets
Posted: 7 Feb 2020
Date Written: January 17, 2020
Protein kinases are drawing great attention in the field of bioinformatics. Tyrosine kinases are mainly responsible for carcinogenesis, by having proliferative actions in the cells when they are over expressed. They enhance the growth and are responsible for the spread of cancer cells. Selected 5-amino Pyrazole substituent and its derivatives (9a-9h) were studied and analyzed for, using flexible ligand docking by Auto Dock 1.5.6 software. The eight ligands (9a-9h) were specifically docked with TrkB (PDB:4AT5), Aurora B(PDB:4AF3), receptor tyrosine(PDB:3PPO), B-Raf(PDB:3D4Q), N-terminal(PDB:2Z7R), Lymphocyte specific (PDB:1QPC), epidermal growth factor tyrosine(PDB: 1M17) and HER2(PDB:1MFL) protein kinases respectively . These proteins are responsible for pancreatic cancer, blood malignancy, lung cancer, breast cancer, colorectal cancer, prostate cancer and they represent the plausible models of their interactions with the anti-cancer agents which are chosen. Further, the candidate ligands were shown to be completely enwrapped in the active site region of proteins via deep docking. From the docking studies it is observed that, N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-3-methoxybenzenesulphonamide(9b), N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-4-tert-butylbenzenesulphonamide(9d), N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-4-tert-butylbenzenesulphonamide(9d), N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-3-methylbenzenesulphonamide(9g), (9d), N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-4-chlorobenzenesulphonamide(9c), (9d), N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-4nitrobenzenesulphonamide(9a) showed minimum binding energies of -11.6,-9.54,-10.82,-10.14,-9.77,-7.68,-10.05,-9.34 kcal/mol respectively with protein targets:TrkB, Aurora B, receptor tyrosine, B-raf, N-terminal, Lymphocyte specific, epidermal growth factor tyrosine and HER2 kinases respectively. The inhibition constants, H-bonds and binding energies were tabulated. N-(1-(4-methoxybenzyl)-3-cyclopropyl-1Hpyrazol-5-yl)-4-tert-butylbenzenesulphonamide(9d) can be the best inhibitor against receptor tyrosine kinase (PDB:3PPO) with better minimum binding energy, ligand efficiency and inhibition constant, when compared to the other ligands. The molecular docking results revealed that these 5-amino Pyrazole derivatives are an outstanding inhibitor of all these protein kinases. All the docked compounds have good ligand efficiency, inhibition constant, vdW+Hbond+desolv energy with best RMSD value. The ligand-macromolecule activity results show that these drugs and N-terminal therapeutic compounds possess a potential antiproliferative drug target actions.
Keywords: Docking results, 5-amino Pyrazole derivatives, protein kinases, inhibition constant
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