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Explicit Treatment of Non‐Michaelis‐Menten and Atypical Kinetics in Early Drug Discovery**
ChemMedChem ( IF 3.4 ) Pub Date : 2020-11-24 , DOI: 10.1002/cmdc.202000791
Bharath Srinivasan 1
Affiliation  

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.

中文翻译:

早期药物发现中非 Michaelis-Menten 和非典型动力学的明确治疗**

生物系统受到高度监管。它们对突然的扰动也有很强的抵抗力,使它们能够维持维持生命所必需的动态平衡。这种稳健性是由影响酶/蛋白质在其细胞环境中的活性以适应不断变化的环境条件的调节机制赋予的。然而,控制酶动力学研究的最初规则主要是针对易于分离和/或重组表达的细胞溶质酶系统进行测试和实施的。此外,这些酶缺乏复杂的调节方式。现在,随着学术实验室和制药公司将注意力转向更复杂的系统(例如,多蛋白复合物、寡聚组装、膜蛋白和翻译后修饰的蛋白质),Michaelis-Menten (MM) 动力学定义的初始公理变得不充分,需要开发一种新的动力学分析来研究这些系统。这篇综述力求概述非典型的酶动力学机制,并且通常不符合经典的 MM 动力学。此外,它还提出了对此类系统的早期药物发现实验的设计和分析的初步想法,以实现对具有理想生理结果的小分子抑制剂的有效筛选和表征。
更新日期:2020-11-24
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