title: In silico investigation of new binding pocket for mitogen activated kinase kinase (MEK): Development of new promising inhibitors.
abstract: It has been previously shown that the inhibition of mitogen activated protein kinase kinase (MEK) contributes to apoptosis and suppression of different cancer cells. Correspondingly, a number of MEK1/2 inhibitors have been designed and evaluated since 2001. However, they did not satisfy essential pharmacokinetic (PK) and pharmacodynamic (PD) properties thus, almost most of them were terminated in pre-clinical or clinical studies. This study aims to design new specific MEK1/2 inhibitors with improved PK/PD profiles to be used as alternative cancer medications. In first part of this study, a comprehensive screening, for the first time, was done on well-known MEK1/2 inhibitors using a number of computational programs such as AutoDock Tools 4.2 (ADT) and AutoDock Vina. Therefore a valuable training dataset as well as a reliable pharmacophore model were provided which were then used to design new inhibitors. According to the results of training dataset, Trametinib was determined as the best inhibitor provided, so far. So, Trametinib was used as the lead structure to design new inhibitors in this study. In second part of this investigation, a set of new allosteric MEK1/2 inhibitors were designed significantly improving the binding energy as well as the ADMET properties, suggesting more specific and stable ligand-receptor complexes. Consequently, the structures 14 and 15 of our inhibitors, as the most potent structures, are great substituents for Trametinib to be used and evaluated in clinical trials as alternative cancer drugs.
authors.affiliation: School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.
authors.forename: Hamed
authors.initials: H
authors.lastname: Yari
authors.affiliation: Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran. Electronic address: m.ganjalikhany@sci.ui.ac.ir.
authors.forename: Mohamad Reza
authors.initials: MR
authors.lastname: Ganjalikhany
authors.affiliation: Center of Equipment Resource for Medical Research & Technology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Sadegh
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D019295:Computational Biology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: 3D-QSAR; ADMET properties; AutoDock; Mitogen activated protein kinase kinase; Vina