Enzyme inhibitors are substances that reduce enzyme activity by interacting with an enzyme or a state of its catalytic cycle. Reversible binding can obstruct substrate association or alter the ability of a substrate-bound enzyme to complete turnover. The relationship between inhibitor binding and the reaction sequence produces characteristic inhibition kinetics [1][2]. Covalent inhibitors possess chemical groups capable of forming a bond with a residue in the target protein [3]. Their selectivity can be assessed across multiple enzymes by measuring competition with activity-based probes, which report accessible, reactive enzyme sites [4]. Recognition interactions position the inhibitor near a susceptible residue, while the inhibitor's reactive group participates in bond formation. Together, these features determine the target engagement and persistence of covalent inhibition [5].
- inhibitor binding
- enzyme kinetics
- partial inhibition
- enzyme inactivation
Enzyme function and inhibition·Molecular Biology·Biochemistry, Genetics and Molecular Biology·Life Sciences
References
- Rona R. Ramsay; Keith F. Tipton; Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs. Molecules 2017, 22, 1192, 10.3390/molecules22071192.
- Geoffrey A. Holdgate; Thomas D. Meek; Rachel L. Grimley; Mechanistic Enzymology in Drug Discovery: A Fresh Perspective. Nat. Rev. Drug Discov. 2017, 17, 115-132, 10.1038/nrd.2017.219.
- Juswinder Singh; Russell C. Petter; Thomas A. Baillie; Adrian Whitty; The Resurgence of Covalent Drugs. Nat. Rev. Drug Discov. 2011, 10, 307-317, 10.1038/nrd3410.
- Micah J. Niphakis; Benjamin F. Cravatt; Enzyme Inhibitor Discovery by Activity-Based Protein Profiling. Annu. Rev. Biochem. 2014, 83, 341-377, 10.1146/annurev-biochem-060713-035708.
- Keriann M. Backus; Bruno E. Correia; Kenneth M. Lum; Stefano Forli; Benjamin D. Horning; Gonzalo E. González-Páez; Sandip Chatterjee; Bryan R. Lanning; John R. Teijaro; Arthur J. Olson; et al. Proteome-wide Covalent Ligand discovery in Native Biological Systems. Nature 2016, 534, 570-574, 10.1038/nature18002.