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J Med Chem. 2018 Mar 22;61(6):2292-2302. doi: 10.1021/acs.jmedchem.7b01408. Epub 2018 Mar 2.

Introduction of Intrinsic Kinetics of Protein-Ligand Interactions and Their Implications for Drug Design.

Author information

1
Department of Biothermodynamics and Drug Design, Institute of Biotechnology , Vilnius University , Saulėtekio 7 , Vilnius , LT-10257 , Lithuania.
2
Department of Chemistry - BMC , Uppsala University , Box 576, Uppsala , SE-751 23 , Sweden.
3
Science for Life Laboratory , Uppsala University , Uppsala , SE-751 23 , Sweden.

Abstract

Structure-kinetic relationship analyses and identification of dominating interactions for optimization of lead compounds should ideally be based on intrinsic rate constants instead of the more easily accessible observed kinetic constants, which also account for binding-linked reactions. The intrinsic rate constants for sulfonamide inhibitors and pharmacologically relevant isoforms of carbonic anhydrase were determined by a novel surface plasmon resonance (SPR) biosensor-based approach, using chemodynamic analysis of binding-linked pH-dependent effects. The observed association rates ( kaobs) were pH-dependent and correlated with the fraction of deprotonated inhibitor and protonated zinc-bound water molecule. The intrinsic association rate constants ( kaintr) were pH independent and higher than kaobs. By contrast, the observed and intrinsic dissociation rate constants were identical and pH-independent, demonstrating that the observed association and dissociation mechanisms are inherently different. A model accounting for the differences between intrinsic and observed rate constants was developed, useful also for other interactions with binding-linked protonation reactions.

PMID:
29466001
DOI:
10.1021/acs.jmedchem.7b01408
[Indexed for MEDLINE]

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