title: Biophysical and physicochemical methods differentiate highly ligand-efficient human D-amino acid oxidase inhibitors.
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 ΔH and ΔS to their ΔG values. Surprisingly, the thermodynamic binding profile of 3 elicited a substantially higher favorable contribution of ΔH to ΔG 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.
authors: Abbott Healthcare Products B.V., Chemical Design & Synthesis Unit, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@kpnmail.nl
authors: Jos H M
authors: JH
authors: Lange
authors: Jennifer
authors: J
authors: Venhorst
authors: Maria J P
authors: MJ
authors: van Dongen
authors: Jurjen
authors: J
authors: Frankena
authors: Firas
authors: F
authors: Bassissi
authors: Natasja M W J
authors: NM
authors: de Bruin
authors: Cathaline
authors: C
authors: den Besten
authors: Stephanie B A
authors: SB
authors: de Beer
authors: Chris
authors: C
authors: Oostenbrink
authors: Natalia
authors: N
authors: Markova
authors: Chris G
authors: CG
authors: Kruse
mesh_terms: D000818:Animals; D002151:Calorimetry / Q000379:methods; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D051381:Rats; D020349:Surface Plasmon Resonance / Q000379:methods; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D003605:D-Amino-Acid Oxidase