Abstract
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 IC50 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.
Highlights
With better healthcare across the world and an ageing population in the developed world, the demand and market for new treatments for complex biological malfunctions, such as neurodegeneration, dementia, and cancer, is enormous
This difference emphasizes the distinction between the equilibrium binding to the oxidized enzyme and the kinetic IC50 that measures the effect of inhibitor binding on catalysis, which depends on the kinetic mechanism involved
It is necessary to show that the inhibition is due to the substrate itself rather than to an inhibitory contaminant. Such contamination has been found to affect assays when the free-base form of benzylamine, obtained from some sources was used for monoamine oxidases (MAO) assays rather than benzylamine appropriate controls to ensure that it is a property of the enzyme and its substrate rather than an artefact arising from failure to control the pH, ionic strength or dielectric of the assay medium correctly
Summary
With better healthcare across the world and an ageing population in the developed world, the demand and market for new treatments for complex biological malfunctions, such as neurodegeneration, dementia, and cancer, is enormous. Structure-based drug design for a single enzyme target has been facilitated, with crystal structures enabling the computational searches of huge chemical databases (reviewed in [4,5]) to identify lead compounds for refinement With such large-scale computational approaches including analysis of off-target activity [6], combining suitable pharmacophores for enzyme combinations such as ChE, MAO and secretases (beta, gamma) for AD is entirely feasible. Such compounds still have to be synthesised and tested experimentally, to confirm the predicted inhibitory effects against each of the targets, before progressing to the complex systems such as cell and in vivo models. The focus of this review is to highlight best practice in the assessment of enzyme inhibition for medicinal chemistry, drawing on examples from our own experience
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