Optimal experimental design for assessment of enzyme kinetics in a drug discovery screening environment
2011 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 5, 858-863 p.Article in journal (Refereed) Published
A penalized ED-optimal design with a discrete parameter distribution was used to find an optimal experimental design for assessment of enzyme kinetics in a screening environment. A data set for enzyme kinetic data (Vmax and Km) was collected from previously reported studies and every Vmax/Km pair (n=76) was taken to represent a unique drug compound. The design was restricted to 15 samples, an incubation time of up to 40 min and starting concentrations (C0) for the incubation between 0.01 and 100 µM. The optimization was performed by finding the sample times and C0 returning the lowest uncertainty (SE) of the model parameter estimates. Individual optimal designs (I-OD), one general optimal design (G-OD) and one for laboratory practice pragmatically modified design (OD) were obtained. In addition, a standard design (STD-D), representing a commonly applied approach for metabolic stability investigations, was constructed. Simulations were performed for OD and STD-D using the Michaelis-Menten (MM) equation and enzyme kinetic parameters were estimated both with MM and a mono exponential (EXP) decay. OD generated a better result (RSE) for 99% of the compounds and an equal or better result (RMSE) for 78% of the compounds. Furthermore, high-quality estimates (RMSE <30%) of both Vmax and Km could be obtained for a considerable number (26%) of the investigated compounds. The results presented in this study demonstrate that the output could generally be improved when compared to that obtained from the standard approaches used today.
Place, publisher, year, edition, pages
2011. Vol. 39, no 5, 858-863 p.
enzyme kinetics, drug discovery screen, optimal experimental design, CLint, Vmax, Km
IdentifiersURN: urn:nbn:se:uu:diva-132347DOI: 10.1124/dmd.110.037309ISI: 000289619600017PubMedID: 21289074OAI: oai:DiVA.org:uu-132347DiVA: diva2:358255