title: Enhancing specificity in the Janus kinases: a study on the thienopyridine JAK2 selective mechanism combined molecular dynamics simulation.
abstract: The selective inhibition for JAK2 over the other JAK family kinases (JAK1, JAK3 and TYK2) has shared an immense challenge due to high conservatism. In this paper, the highly JAK2 selective mechanism of the thienopyridine derivative was identified at the molecular level, based on insights into the inhibitory effects of compound on four JAK kinases by molecular docking, molecular dynamic simulations, free energy calculation and decomposition. The results clearly indicated that the nonpolar contribution and the H-bond network in the hinge region played a critical selective role in stabilizing ligand JAK2, and the residues Glu930, Leu932 and Gly935 in JAK2 kinase were the key differences compared to the equivalence residues of JAK1, JAK3 and TYK2, which were further verified by simulating four complexes of JAK kinases with another highly selective thienopyridine JAK2 inhibitor . Finally, several novel molecules were designed according to above findings and further verified by the same comprehensive modeling protocol. The obtained results not only demonstrated the rationality of our models and analyses, but also suggested that the designed molecules with higher JAK2 selectivity and bioactivity potential would provide an update of JAK2 inhibitors.
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China. zhaihl@163.com.
authors.forename: Jiao Jiao
authors.initials: JJ
authors.lastname: Li
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China. zhaihl@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China. zhaihl@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Tu
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China. zhaihl@163.com.
authors.forename: Hong Lin
authors.initials: HL
authors.lastname: Zhai
authors.affiliation: College of Chemistry & Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China. zhaihl@163.com.
authors.forename: Xiao Yun
authors.initials: XY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; C446540:thienopyridine; C507924:JAK2 protein, human; D053614:Janus Kinase 2