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Docking and Molecular Dynamics Study on the Inhibitory Activity of Novel Inhibitors on Epidermal Growth Factor Receptor (EGFR)

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EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape - stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer.

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Keywords: 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues; AMBER force field; ATP binding; Cetuximab; EGFR; EGFR inhibitors; EGFR-related cancers; Erlotinib; Gasteiger charges; Gefitinib; H-bond interactions; La-patinib; Lamarckian genetic algorithm (LGA); Matuzumab; Panitumumab; SHAKE algorithm; X-ray crystallography; allosteric transition; anti-EGFR drugs; anti-cancer drugs; binding free energy (Ebinding); binding mechanism; binding site; bio-macromolecular internal collective; biologic activity; cancer; cell proliferation; cell-surface receptor; cellular responding; competitive inhibitors; crystallographical structure; diffusion-controlled reaction; docked energy; drug design; ectodomain-binding domain; extracellular ligand binding region; hydrophobic amino acids; hydrophobic interactions; intercalation of drugs; intracellular kinase domain; membrane protein type predic-tion; molecular docking; molecular dynamics; monoclonal antibodies; oncogenic activity; particle mesh Ewald method; phosphorylation; pro-tein-ligand complexes; protease type prediction; protein cleavage site prediction; signal peptide prediction; solvent interface; stacking interaction; steric effect; thiazolopyrimidine ring; tissue homeostasis; transmembrane segment; tumorigenesis; tyrosine kinase inhibitors

Document Type: Research Article

Publication date: January 1, 2011

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