Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 7; p. 1192
• Main Authors: Ramsay, Rona R, Tipton, Keith F
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.07.2017; MDPI
• Subjects: Alzheimer’s disease; Amine oxidase (flavin-containing); Animals; Cholinesterase; Cholinesterase inhibitors; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cholinesterases - chemistry; Cholinesterases - metabolism; Computer Simulation; donepezil; Drug development; Drug Discovery - methods; Drug Evaluation, Preclinical; Drugs; Enzymatic activity; Enzyme Activation - drug effects; enzyme inhibition; Enzymes; galantamine; Humans; Inhibition; inhibitor constant; l-deprenyl (selegiline); Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Monoamine Oxidase Inhibitors - therapeutic use; multitarget-directed ligand (MTDL); Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurotransmitter Agents - antagonists & inhibitors; Neurotransmitter Agents - metabolism; Pharmacology; rasagiline; Review; rivastigmine; Structure-Activity Relationship; rasagiline; inhibitor constant; l-deprenyl (selegiline); rivastigmine; Alzheimer’s disease; enzyme inhibition; donepezil; multitarget-directed ligand (MTDL); galantamine
• DOI: 10.3390/molecules22071192
• ISSN: 1420-3049

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.