title: In silico screening and study of novel ERK2 inhibitors using 3D QSAR, docking and molecular dynamics.
abstract: ERK2 is a dual specificity protein kinase, part of the Ras/Raf/MEK/ERK signal transduction cascade. It forms an interesting target for inhibition based on its relationship with cell proliferation and oncogenesis. A 3D QSAR pharmacophore model (Hypo1) with high correlation (r=0.938) was developed for ERK2 ATP site on the basis of experimentally known inhibitors. The model included three hydrogen bonds, and one hydrophobic site. Assessment of Hypo1 through Fisher randomization, cost analysis, leave one out method and decoy test suggested that the model can reliably detect ERK2 inhibitors. Hypo1 has been used for virtual screening of potential inhibitors from ZINC, Drug Bank, NCI, Maybridge and Chembank databases. Using Hypo1 as a query, databases have been interrogated for compounds who meet the pharmacophore features. The resulting hit compounds were subject to docking and analysis. Docking and molecular dynamics analysis showed that in order to achieve a higher potency compounds have to interact with catalytic site, glycine rich loop, Hinge region, Gatekeeper region and ATP site entrance residues. We also identified catalytic site and Glycine rich loop as important regions to bind by molecules for better potency and selectivity.
authors: Metabolic Biophysics and Applied Pharmacology Laboratory, Department of Biophysics, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia. Electronic address: Larifsofiene@gmail.com.
authors: Sofiene
authors: S
authors: Larif
authors: Department of Clinical Pharmacology, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia.
authors: Chaker Ben
authors: CB
authors: Salem
authors: Department of Clinical Pharmacology, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia.
authors: Houssem
authors: H
authors: Hmouda
authors: Department of Clinical Pharmacology, Faculty of Medicine of Sousse, 4002 Sousse, Tunisia.
authors: Kamel
authors: K
authors: Bouraoui
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
keywords: 3D QSAR pharmacophore; ERK2; HypoGen; LigandFit; Molecular docking; Molecular dynamics