title: In silico design: extended molecular dynamic simulations of a new series of dually acting inhibitors against EGFR and HER2.
abstract: Based 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.
authors.affiliation: eChemistry Laboratory, Faculty of Life and Social Sciences, Swinburne University of Technology, Hawthorn, Melbourne, Victoria 3122, Australia. mmahmed@swin.edu.au
authors.forename: Marawan
authors.initials: M
authors.lastname: Ahmed
authors.forename: Maiada M
authors.initials: MM
authors.lastname: Sadek
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Abouzid
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D066246:ErbB Receptors; D008024:Ligands; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D014867:Water
keywords: AM1-D; EGFR/HER2; Molecular dynamics; Tyrosine kinase; Water occupancy