Fluxes for Unraveling Complex Binding Mechanisms. (December 2020)

• Record Type: Journal Article
• Authors: Vauquelin, Georges; Maes, Dominique; Swinney, David C.
• Is Part Of: Trends in pharmacological sciences. Volume 41:Number 12(2020)
• Page Start: 923
• Page End: 932
• Publication Date: 2020-12
• Subjects: binding fluxes -- conformational selection -- induced fit -- nonequilibrium -- rate constants -- thermodynamic cycle; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2020.10.003
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : 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 interest, but published data still merely refer to the peculiar situation of equilibrium binding. This article draws attention to the benefit of extending those approaches to address more physiological nonequilibrium binding conditions and in vivo situations. For the presented example, they help to apprehend transient experimental manifestations of a 'conventional' thermodynamic cycle. Highlights: Induced-fit and conformational selection mechanisms for ligand binding were long considered to be mutually exclusive, and most of the slowly dissociating drugs were proposed to act in an induced-fit-like manner. Yet, both pathways form a thermodynamic cycle. Inspection with the aid of binding flux-based approaches contributed to the current view that they act in unison and even that the dominance of one or the other depends on the ligand concentration. Those are now increasingly adopted and even extended. Yet, published data still refer to equilibrium binding, which is hardly met in vivo . This calls for extending those approaches to nonequilibrium situations. Current cycle-based simulations illustrate the utility of such extensions. They highlight their benefit for apprehending transient and occasionally even unexpected manifestations of complex binding mechanisms in vitro and in vivo .