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Induced fit versus conformational selection Vrije Universiteit Brussel

Georges Vauquelin, Dominique Maes

Induced fit- (IF) and conformational selection (CS) binding mechanisms have long been regarded to be mutually exclusive. Yet, they are now increasingly considered to produce the final ligand-target complex alongside within a thermodynamic cycle. This viewpoint benefited from the introduction of binding fluxes as a tool for analyzing the overall behavior of such cycle. This study aims to provide more vivid and applicable insights into this ...

Fluxes for Unraveling Complex Binding Mechanisms Vrije Universiteit Brussel

Georges Vauquelin, Dominique Maes, David C Swinney

A decade ago, many high-affinity drugs were thought to bind to their target via an induced-fit pathway instead of conformational selection. Yet, both pathways make up part of a thermodynamic cycle, and, owing to binding flux-based approaches, it is now rather considered that they act in parallel and also that their relative contribution to the final ligand-target complex depends on the ligand concentration. Those approaches are of increasing ...

Distinct in vivo target occupancy by bivalent- and induced-fit-like binding drugs Vrije Universiteit Brussel

Georges Vauquelin

Background and Purpose: Optimal drug therapy often requires long-lasting target occupancy While this attribute was usually linked to the drug's pharmacokinetic properties, the dissociation rate is now increasingly recognized to contribute as well. Nearly all the earlier pharmacokinetic-pharmacodynamic (PK-PD) simulations encompassed single-step binding drugs and focused on koff. However, ‘micro’-PK mechanisms and more complex binding ...

"Partial" competition of heterobivalent ligand binding may be mistaken for allosteric interactions: A comparison of different target interaction models Vrije Universiteit Brussel

Georges Vauquelin, David Hall, Steven Charlton
Background and Purpose: Non-competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought-after advantages include a ceiling level to the drug effect and greater receptor subtype-selectivity. It is thus important to determine the mode of interaction of newly identified receptor ligands early in the drug discovery process and binding studies with labeled orthosteric ...

Case study: Angiotensin receptor blockers (ARBs) Vrije Universiteit Brussel

Georges Vauquelin
here is now also ample evidence that the "residence time" of a drug at it cellular target (such as a receptor or an enzyme) may affect its clinical performance. In this respect, a great deal of attention has been devoted to those situations in where optimal clinical performance requires continuing, high levels of target occupancy. This has for example been proposed to be the case with AT1 receptor antagonist candesartan.

Experimental Methods to Determine Binding Kinetics Vrije Universiteit Brussel

Georges Vauquelin, Walter Huber, David Swinney
Drugs interact with proteins and that interaction leads to the pharmacological
response. The interaction involves an initial binding of the drug to the protein,
described by the second order association rate constant, k on and debinding,
described by the ?rst-order dissociation rate constant, k o? . The a?nity of the
drug for the protein is de?ned by the equilibrium dissociation constant, K d ,
which equals k o? /k on . ...

Avidity and positive allosteric modulation/cooperativity act hand in hand to increase the residence time of bivalent receptor ligands. doi: 10.1111/fcp.12052 Vrije Universiteit Brussel

Georges Vauquelin, Giampiero Bricca, Isabelle Van Liefde
Bivalent ligands bear two target-binding pharmacophores. Their simultaneous binding increases their affinity (avidity) and residence time. They become "bitopic" when the pharmacophores exert allosteric modulation of each other's affinity and/or activity.
Present simulations reveal that positive cooperativity exacerbates these phenomena whereas negative cooperativity curtails them, irrespective of whether the association- or dissociation ...

A study into the molecular mechanism of binding kinetics and long residence times of human CCR5 receptor antagonists Vrije Universiteit Brussel

Swinney Davids, P. Beavis, Chuang Kt, Y. Zheng, I. Lee, P. Gee, J. Deval, Rotstein Dm, M. Dioszegi, P. Ravendran, et al.
Background and purpose. CCR5 is a coreceptor for HIV-1 infection and target for anti-viral therapy. A greater understanding of the binding kinetics of small molecule allosteric ligand interaction with CCR5 will lead to a better understanding of the binding process and may help discover new molecules that avoid resistance.
Experimental approach. Using [3H] maraviroc as a radioligand, a number of different binding protocols were employed in ...

Molecular mechanism of allosteric modulation: insight from a binding kinetics study at the human adenosine A1 receptor Vrije Universiteit Brussel

D. Deval, No name available, A. Massink, Van Velthoven Jpd, Georges Vauquelin, Ijzerman Ap, Heitman Lh
Background and purpose: Many G protein-coupled receptors (GPCRs) can be allosterically modulated by small molecule ligands. This modulation is best understood in terms of the kinetics of the ligand-receptor interaction. However, many current kinetic assays require at least the (radio-) labeling of the orthosteric ligand, which is impractical for studying a range of ligands. Here we describe the application of a so-called competition association ...

[3H]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase Vrije Universiteit Brussel

Alexandros Nikolaou, Isabelle Van Den Eynde, Dirk Tourwe, Georges Vauquelin, Géza Tóth, Jayapal Reddy Mallareddy, Marko Poglitsch, Jo Van Ginderachter, Patrick Vanderheyden

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Ang IV also acts as a weak agonist for the Ang II-receptor (AT1), implying the need for ...