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Lange, JH; Venhorst, J; van Dongen, MJ; Frankena, J; Bassissi, F; de Bruin, NM; den Besten, C; de Beer, SB; Oostenbrink, C; Markova, N; Kruse, CG.
(2011): Biophysical and physicochemical methods differentiate highly ligand-efficient human D-amino acid oxidase inhibitors.
Eur J Med Chem. 2011; 46(10):4808-4819 FullText FullText_BOKU

Abstract:: Many early drug research efforts are too reductionist thereby not delivering key parameters such as kinetics and thermodynamics of target ligand binding. A set of human D-Amino Acid Oxidase (DAAO) inhibitors 1-6 was applied to demonstrate the impact of key biophysical techniques and physicochemical methods in the differentiation of chemical entities that cannot be adequately distinguished on the basis of their normalized potency (ligand efficiency) values. The resulting biophysical and physicochemical data were related to relevant pharmacodynamic and pharmacokinetic properties. Surface Plasmon Resonance data indicated prolonged target ligand residence times for 5 and 6 as compared to 1-4, based on the observed k(off) values. The Isothermal Titration Calorimetry-derived thermodynamic binding profiles of 1-6 to the DAAO enzyme revealed favorable contributions of both Delta H and Delta S to their Delta G values. Surprisingly, the thermodynamic binding profile of 3 elicited a substantially higher favorable contribution of Delta H to Delta in comparison with the structurally closely related fused bicyclic acid 4. Molecular dynamics simulations and free energy calculations of 1, 3, and 4 led to novel insights into the thermodynamic properties of the binding process at an atomic level and in the different thermodynamic signatures of 3 and 4. The presented holistic approach is anticipated to facilitate the identification of compounds with best-in-class properties at an early research stage. (C) 2011 Elsevier Masson SAS. All rights reserved.
Authors BOKU Wien:: Oostenbrink Chris
Find related publications in this database (Keywords): D-amino acid oxidase; Biophysical techniques; Surface plasmon resonance; Isothermal titration calorimetry; Binding thermodynamics; Molecular dynamics simulations; Best-in-class compounds; Enzyme inhibitor; Holistic approach