title: Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free energy calculations.
abstract: Focal adhesion kinase is an important target for the treatment of many kinds of cancers. Inhibitors of FAK are proposed to be the anticancer agents for multiple tumors. The interaction characteristic between FAK and its inhibitors is crucial to develop new inhibitors. In the present article, we used Molecular Dynamic (MD) simulation method to explore the characteristic of interaction between FAK and three inhibitors (PHM16, TAE226, and ligand3). The MD simulation results together with MM-GB/SA calculations show that the combinations are enthalpy-driven process. Cys502 and Asp564 are both essential residues due to the hydrogen bond interactions with inhibitors, which was in good agreement with experimental data. Glu500 can form a non-classical hydrogen bond with each inhibitor. Arg426 can form electrostatic interactions with PHM16 and ligand3, while weaker with TAE226. The electronic static potential was employed, and we found that the ortho-position methoxy of TAE226 has a weaker negative charge than the meta-position one in PHM16 or ligand3. Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563 Leu567, Ser568 are all crucial residues in hydrophobic interactions. The key residues in this work will be available for further inhibitor design of FAK and also give assistance to further research of cancer.
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Jiu-Yu
authors.initials: JY
authors.lastname: Zhan
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: c Changchun Institute of Biological Products Co. Ltd , Changchun 130012 , P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.|b Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , Jilin University , Changchun 130023 , P.R. China.
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: MM-GB/SA calculation; electronic static potential; focal adhesion kinase; hydrophobic interaction; inhibitor; molecular dynamic simulation