Explicit Treatment of Non‐Michaelis‐Menten and Atypical Kinetics in Early Drug Discovery

Biological systems are highly regulated. They are also highly resistant to sudden perturbations enabling them to maintain the dynamic equilibrium essential to sustain 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 mostly tested and implemented for 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, multiprotein 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. This 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. Update and adapt: The success of drug‐discovery relies on characterizing the kinetics and thermodynamics of a drug's interaction with its protein target. The methodologies applied are based on the Michaelis‐Menten model; however, with increasing complexity of the enzymes and complexes being studied, the model needs to be adapted to accurately characterize their kinetic behaviour and appropriately inform drug‐discovery initiatives.