Investigation of the effect of molecular properties on the binding kinetics of a ligand to its biological target

Miller, D. Craig; Lunn, Graham; Jones, Peter; Sabnis, Yogesh; Davies, Nichola L.; Driscoll, Paul C.

doi:10.1039/c2md00270a

Cited by 50 publications

(57 citation statements)

References 13 publications

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“…[17] In ar ough approximation, more rotatable bonds and higherm olecular weights correlate with long complex half-lives. [18] Moreover, water-shielded hydrogen bonds also tend to improve the lifetime of proteinligand complexes. [19] On the other hand, the on-rate is limited by diffusion and can be influenced by steric and electrostatic factors as well as conformational dynamics.…”

Section: Introductionmentioning

confidence: 99%

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

Zihlmann

Silbermann

Sharpe

et al. 2018

Chemistry A European J

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Affinity data, such as dissociation constants (K ) or inhibitory concentrations (IC ), are widely used in drug discovery. However, these parameters describe an equilibrium state, which is often not established in vivo due to pharmacokinetic effects and they are therefore not necessarily sufficient for evaluating drug efficacy. More accurate indicators for pharmacological activity are the kinetics of binding processes, as they shed light on the rate of formation of protein-ligand complexes and their half-life. Nonetheless, although highly desirable for medicinal chemistry programs, studies on structure-kinetic relationships (SKR) are still rare. With the recently introduced analytical tool kinITC this situation may change, since not only thermodynamic but also kinetic information of the binding process can be deduced from isothermal titration calorimetry (ITC) experiments. Using kinITC, ITC data of 29 mannosides binding to the bacterial adhesin FimH were re-analyzed to make their binding kinetics accessible. To validate these kinetic data, surface plasmon resonance (SPR) experiments were conducted. The kinetic analysis by kinITC revealed that the nanomolar affinities of the FimH antagonists arise from both (i) an optimized interaction between protein and ligand in the bound state (reduced off-rate constant k ) and (ii) a stabilization of the transition state or a destabilization of the unbound state (increased on-rate constant k ). Based on congeneric ligand modifications and structural input from co-crystal structures, a strong relationship between the formed hydrogen-bond network and k could be concluded, whereas electrostatic interactions and conformational restrictions upon binding were found to have mainly an impact on k .

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Section: Introductionmentioning

confidence: 99%

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

Zihlmann

Silbermann

Sharpe

et al. 2018

Chemistry A European J

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show abstract

“…In such a fortunate case, the inconvenient and theoretically cumbersome property entropy would cancel out in a relative comparison and affinity or free energy would only correlate with enthalpy. [11,12] Nonetheless, can an affinity-driven drug discovery and lead optimization campaign profit from additional details explaining why a particular affinity is obtained? In contrast, the cumbersome entropy captures changes in the ordering parameters and how the energy content of a system is distributed across the multiple degrees of freedom of a system that comprises many conformational and configurational states that will be distinctly populated and contribute jointly to the partition function.…”

mentioning

confidence: 99%

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

Klebe

2014

ChemMedChem

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The prime property to rate the success of hit-to-lead-to-drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of koff and kon of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics- or kinetics-structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity.

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“…The association and dissociation pathways revealed by computational simulations in combination with experimental studies (e.g. mutagenesis data and biophysical measurements ) can in time be used to relate ligand structure to kinetic properties, thereby changing the focus from solely affinity-based optimizations to optimization of kinetic properties (Tresadern et al 2011;Miller et al 2012). As discussed in Sect.…”

Section: Gpcr-ligand Interaction Space In More Detailmentioning

confidence: 99%

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

Kooistra¹,

Leurs²,

Esch³

et al. 2013

Advances in Experimental Medicine and Biology

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This chapter will focus on G protein-coupled receptor structure-based virtual screening and ligand design. A generic virtual screening workflow and its individual elements will be introduced, covering amongst others the use of experimental data to steer the virtual screening process, ligand binding mode prediction, virtual screening for novel ligands, and rational structure-based virtual screening hit optimization. An overview of recent successful structure-based ligand discovery and design studies shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands for GPCRs. Moreover, the recently solved GPCR crystal structures have further increased the opportunities in structure-based ligand discovery for this pharmaceutically important protein family. The current chapter will discuss several challenges in rational ligand discovery based on GPCR structures including: (i) structure-based identification of ligands with specific effects on GPCR mediated signaling pathways, and (ii) virtual screening and structure-based optimization of fragment-like molecules.

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Investigation of the effect of molecular properties on the binding kinetics of a ligand to its biological target

Cited by 50 publications

References 13 publications

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

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