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Explicit Treatment of Non Michaelis-Menten and Atypical Kinetics in Early Drug Discovery
: Received: 7 October 2020 / Approved: 8 October 2020 / Online: 8 October 2020 (13:34:16 CEST)
A peer-reviewed article of this Preprint also exists.
Journal reference: ChemMedChem 2020
Biological systems are highly regulated. They are also highly resistant to sudden perturbations enabling them to maintain the dynamic equilibrium essential for sustenance of life. This robustness is conferred by regulatory mechanisms that influence the activity of enzymes/proteins within their cellular context, to adapt to changing environmental conditions. However, the initial rules governing the study of enzyme kinetics were tested and implemented for mostly cytosolic enzyme systems that were easy to isolate and/or recombinantly express. Moreover, these enzymes lacked complex regulatory modalities. Now, with academic labs and pharmaceutical companies turning their attention to more complex systems (for instance, multi-protein complexes, oligomeric assemblies, membrane proteins and post-translationally modified proteins), the initial axioms defined by Michaelis-Menten (MM) kinetics are rendered inadequate and the development of a new kind of kinetic analysis to study these systems is required. The current review strives to present an overview of enzyme kinetic mechanisms that are atypical and, oftentimes, do not conform to the classical MM kinetics. Further, it presents initial ideas on the design and analysis of experiments in early drug-discovery for such systems, to enable effective screening and characterisation of small-molecule inhibitors with desirable physiological outcomes.
Non Michaelis-Menten Kinetics; High-throughput screening; allostery; cooperativity; processive kinetics; distributive kinetics; single-molecule; auto-catalytic; drug discovery
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