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KinITC-One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4483794
Author(s) Zihlmann, Pascal; Silbermann, Marleen; Sharpe, Timothy; Jiang, Xiaohua; Mühlethaler, Tobias; Jakob, Roman P.; Rabbani, Said; Sager, Christoph P.; Frei, Priska; Pang, Lijuan; Maier, Timm; Ernst, Beat
Author(s) at UniBasel Maier, Timm
Ernst, Beat
Zihlmann, Pascal
Silbermann, Marleen
Sharpe, Timothy
Jiang, Xiaohua
Mühlethaler, Tobias
Jakob, Roman Peter
Rabbani, Said
Sager, Christoph
Frei, Priska
Pang, Lijuan
Year 2018
Title KinITC-One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists
Journal Chemistry (Weinheim an der Bergstrasse, Germany)
Volume 24
Number 49
Pages / Article-Number 13049-13057
Mesh terms Adhesins, Escherichia coli, chemistry; Calorimetry, methods; Drug Discovery; Fimbriae Proteins, chemistry; Hydrogen Bonding; Kinetics; Ligands; Mannosides, chemistry; Models, Molecular; Protein Binding; Protein Conformation; Protein Domains; Structure-Activity Relationship; Thermodynamics
Abstract Affinity data, such as dissociation constants (K; D; ) or inhibitory concentrations (IC; 50; ), 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; off; ) and (ii) a stabilization of the transition state or a destabilization of the unbound state (increased on-rate constant k; on; ). Based on congeneric ligand modifications and structural input from co-crystal structures, a strong relationship between the formed hydrogen-bond network and k; off; could be concluded, whereas electrostatic interactions and conformational restrictions upon binding were found to have mainly an impact on k; on; .
Publisher WILEY-V C H VERLAG GMBH
ISSN/ISBN 1521-3765
edoc-URL https://edoc.unibas.ch/65291/
Full Text on edoc No
Digital Object Identifier DOI 10.1002/chem.201802599
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/29939458
ISI-Number WOS:000443382500038
Document type (ISI) Journal Article
 
   

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