Lead identification and docking studies of metastatic protein human mitogen activated protein kinase kinase4

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AbstractHuman dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4) is a direct activator of MAP kinases in response to various environmental stresses or mitogenic stimuli. Upon phosphorylation, MAP2K4 has been shown to activate MAPK8, MAPK9 and MAPK14/p38 but not MAPK1/ERK2 or MAPK3/ERK1. Over expression of MAP2K4 causes carcinogenic effects, such as ovarian cancer, colorectal cancer, prostate cancer and pancreatic cancer. Our present study was carried out to design a potent drug molecule against MAP2K4 to control over expression. As there is no experimentally determined structure for MAP2K4, the homology modeling technique of Modeller9v7 was implemented to generate a MAP2K4 3D model based on the co-crystal structure of MAP2K6 (PDB ID: 3FME) with staurosporine. Twenty such models obtained were accessed through DOPE score, PROCHECK, ProSA and the highly reliable model was further optimized for virtual screening in Maestro v9.0 applying OPLS2001 force field. MAP2K4 specific inhibitors such as staurosporine, genistein and cayanidin were selected and screened against one million entries of the Ligand.Info Meta-Database, to generate an in house library of 1151 analogs. LigPrep was used to generate multiple conformations of the in-house ligands. In an effort to ensure good ADMET properties of the selected ligands Lipinski filter and reactive filter was applied. The strategic computational docking using Glide v5.5 ranked 10 lead molecules with good binding affinity with MAP2K4. Among ten lead molecules Lead ‘1’, Lead ‘2’, Lead ‘3’ had higher binding affinity than the published inhibitors. The scores for Lead ‘1’ -8.75, Lead ‘2’ -8.54, Lead ‘3’ -7.96 and scores for published inhibitors are STAUROSPORINE: -6.55; GENISTEIN: -6.42 and CAYANIDINE: -6.24. So Lead ‘1’ with the lowest docking score (-8.75kcal/mol) is the best ligand for protein functional activity inhibition. Lead ‘1’ directly binds to the MAP2K4 protein by forming strong hydrogen bonds with LYS-131, LEU-180, LYS-231, ASP-229. So we can consider that the lead ‘1’ molecule can act as a potent inhibitor for MAP2K4.