Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket.
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.
Frédérick
Raphaël
R
Department of Pharmacy, Drug Design and Discovery Center, University of Namur, FUNDP, 61, rue de Bruxelles, B-5000 Namur, Belgium.
Charlier
Caroline
C
Robert
Séverine
S
Wouters
Johan
J
Masereel
Bernard
B
Pochet
Lionel
L
D000991:Antithrombins / Q000737:chemistry*; D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry*; D008958:Models, Molecular; D014867:Water / Q000737:chemistry*
D000991:Antithrombins; D003374:Coumarins; D014867:Water; C030123:coumarin