title: Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket.
abstract: The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives.
authors.affiliation: Department of Pharmacy, Drug Design and Discovery Center, University of Namur, FUNDP, 61, rue de Bruxelles, B-5000 Namur, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Caroline
authors.initials: C
authors.lastname: Charlier
authors.forename: Séverine
authors.initials: S
authors.lastname: Robert
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Lionel
authors.initials: L
authors.lastname: Pochet
mesh_terms: D000991:Antithrombins / Q000737:chemistry*; D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry*; D008958:Models, Molecular; D014867:Water / Q000737:chemistry*
chemical_list: D000991:Antithrombins; D003374:Coumarins; D014867:Water; C030123:coumarin