Ahmed M.Sadek M.M.Abouzid K.A.Wang F.Chemistry LaboratoryFaculty of Life and Social SciencesSwinburne University of TechnologyHawthornMelbourneVIC 3122Australia; Pharmaceutical Organic ChemistryFaculty of PharmacyMSA UniversityEgypt; Pharmaceutical Chemistry DepartmentFaculty of PharmacyAin Shams UniversityCairo 11566Egypt2020-01-092020-01-09201310933263https://doi.org/10.1016/j.jmgm.2013.06.004PubMed ID 23911931https://t.ly/ndwzeScopusBased on the hit structures that have been identified in our previous studies against EGFR and HER2, new potential inhibitors that share the same scaffold of the hit structures are designed and screened in silico. Insights into understanding the potential inhibitory effect of the new inhibitors against both EGFR and HER2 receptors is obtained using extended molecular dynamics (MD) simulations and different scoring techniques. The binding mechanisms and dynamics are detailed with respect to two approved inhibitors against EGFR (lapatinib) and HER2 (SYR127063). The best scoring inhibitor (T9) is chosen for additional in silico investigation against both the wild-type and T790M mutant strain of EGFR and the wild-type HER2. The results reveal that certain substitution patterns increase the stability and assure stronger binding and higher H-bond occupancy of the conserved water molecule that is commonly observed with kinase crystal structures. Furthermore, the new inhibitor (T9) forms stable interactions with the mutant strain as a direct consequence of the enhanced ability to form additional hydrogen bonding interactions with binding site residues. 2013 Elsevier Ltd. All rights reserved.EnglishOctober University for Modern Sciences and Artsجامعة أكتوبر للعلوم الحديثة والآدابUniversity of Modern Sciences and ArtsMSA UniversityAM1-DEGFR/HER2Molecular dynamicsTyrosine kinaseWater occupancyAmino acidsBinsEnzymesHydrogen bondsMoleculesScaffoldsBinding mechanismsEGFR/HER2Hydrogen bonding interactionsMolecular dynamics simulationsPotential inhibitorsScoring techniquesSubstitution patternsTyrosine kinaseMolecular dynamicsepidermal growth factor receptor kinase inhibitorerlotinibgefitiniblapatinibprotein tyrosine kinase inhibitorquinazoline derivativesyr 127063unclassified drugarticlebinding sitecrystal structurehydrogen bondmolecular dynamicsnonhumanpriority journalsimulationAM1-DEGFR/HER2Molecular dynamicsTyrosine kinaseWater occupancyBinding SitesComputer SimulationDrug DesignHumansLigandsMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationProtein BindingProtein Kinase InhibitorsQuantitative Structure-Activity RelationshipReceptor, Epidermal Growth FactorReceptor, erbB-2WaterArticlehttps://doi.org/10.1016/j.jmgm.2013.06.004PubMed ID 23911931