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Explicit Treatment of Non‐Michaelis‐Menten and Atypical Kinetics in Early Drug Discovery **
Author(s) -
Srinivasan Bharath
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000791
Subject(s) - robustness (evolution) , kinetics , enzyme kinetics , context (archaeology) , computational biology , enzyme , biochemical engineering , small molecule , systems biology , drug discovery , chemistry , living systems , axiom , biochemistry , biophysics , biology , computer science , engineering , artificial intelligence , active site , mathematics , gene , paleontology , physics , geometry , quantum mechanics
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.