title: High performance enzyme kinetics of turnover, activation and inhibition for translational drug discovery.
abstract: Enzymes are the macromolecular catalysts of many living processes and represent a sizable proportion of all druggable biological targets. Enzymology has been practiced just over a century during which much progress has been made in both the identification of new enzymes and the development of novel methodologies for enzyme kinetics. Areas covered: This review aims to address several key practical aspects in enzyme kinetics in reference to translational drug discovery research. The authors first define what constitutes a high performance enzyme kinetic assay. The authors then review the best practices for turnover, activation and inhibition kinetics to derive critical parameters guiding drug discovery. Notably, the authors recommend global progress curve analysis of dose/time dependence employing an integrated Michaelis-Menten equation and global curve fitting of dose/dose dependence. Expert opinion: The authors believe that in vivo enzyme and substrate abundance and their dynamics, binding modality, drug binding kinetics and enzyme's position in metabolic networks should be assessed to gauge the translational impact on drug efficacy and safety. Integrating these factors in a systems biology and systems pharmacology model should facilitate translational drug discovery.
authors: a Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. , Kenilworth , NJ , USA.
authors: Rumin
authors: R
authors: Zhang
authors: a Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. , Kenilworth , NJ , USA.
authors: Kenny
authors: K
authors: Wong
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010600:Pharmacology; D049490:Systems Biology / Q000379:methods; D057170:Translational Research, Biomedical / Q000379:methods*
chemical_list: D004798:Enzymes; D004364:Pharmaceutical Preparations
keywords: High performance enzyme assay; Michaelis-Menten enzyme kinetics; active site titration; binding kinetics; binding modality; closed forms of Michaelis-Menten equation; drug discovery; enzyme activation; enzyme inhibition; global curve fitting; global progress curve analysis; pharmacodynamics; quasi-steady-state approximation; target abundance