title: The unbinding studies of vascular endothelial growth factor receptor-2 protein tyrosine kinase type II inhibitors.
abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase has two conformations, active and inactive conformations. Type II inhibitors bind to inactive conformation. It has two possible binding/unbinding paths. To explore the unbinding path of inhibitor 01-435 that was generated by fragment build in the binding pocket of VEGFR-2, molecular dynamics (MD) simulation was performed on the crystal structure of VEGFR-2 in complex with 01-435, then steered molecular dynamics (SMD) simulation was executed on the crystal structure of VEGFR-2 in complex with 01-435. Pull force, van der Waals and electrostatic interaction along the two paths were calculated by using SMD simulation. The SMD simulation results indicate that the more favorable path for inhibitor dissociation is along with the traditional ATP-channel rather than the allosteric-pocket-channel, which is mainly due to the less electrostatic interaction that the ligand suffers during dissociation process along the traditional ATP-channel.
authors.affiliation: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China.
authors.forename: Cong-min
authors.initials: CM
authors.lastname: Kang
authors.affiliation: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China.
authors.forename: Dong-qing
authors.initials: DQ
authors.lastname: Liu
authors.affiliation: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China.
authors.forename: Xin-ying
authors.initials: XY
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Ocean University of China, Qingdao 266003, PR China.
authors.forename: Ri-lei
authors.initials: RL
authors.lastname: Yu
authors.affiliation: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, PR China. Electronic address: lvyingtao@qust.edu.cn.
authors.forename: Ying-tao
authors.initials: YT
authors.lastname: Lv
mesh_terms: D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D055672:Static Electricity; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Electrostatic interaction; Fragment build; Pull force; SMD; VEGFR-2