title: Evaluation of interactions between urokinase plasminogen and inhibitors using molecular dynamic simulation and free-energy calculation.
abstract: The binding modes of urokinase-type plasminogen activator (uPA) with five inhibitors (1-(7-sulfonamidoisoquinolinyl) guanidine derivatives) were predicted based on molecular dynamic simulations. MM/PBSA free-energy calculations and MM/GBSA free-energy decomposition analyses were performed on the studied complexes. The calculated binding free energies are reasonably consistent with the experimental results. The free-energy decomposition analyses elucidate the different contributions of the energy of some favorable residues in the interactions between protein and ligand of each complex. The results indicate that the inhibitors mainly interact with the S1 pocket of uPA, wherein the hydrogen bonds and the interactions between guanidines and the corresponding residues play an important role. Moreover, hydrogen bond analyses show the water-mediated hydrogen-bond network near the S1 pocket between uPA, and the ligand probably leads to excellent selectivity of these inhibitors on uPA.
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter , 155 Yangqiao Road West, Fuzhou, Fujian 350002, People's Republic of China.
authors.forename: Rongjian
authors.initials: R
authors.lastname: Sa
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Mingdong
authors.initials: M
authors.lastname: Huang
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Li
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wei
authors.forename: Kechen
authors.initials: K
authors.lastname: Wu
mesh_terms: D006146:Guanidines / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding; D055672:Static Electricity; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D006146:Guanidines; D011480:Protease Inhibitors; D014867:Water; D014568:Urokinase-Type Plasminogen Activator