High-resolution dose-response screening using droplet-based microfluidics

Oliver Miller (1) , Abdeslam El Harrak , Thomas Mangeat (2) , Jean-Christophe Baret (3) , Lucas Frenz (1) , Bachir El Debs , Estelle Mayot (4) , Michael L Samuels , Eamonn K Rooney , Pierre Dieu , Martin Galvan , Darren R Link , Andrew D Griffiths

1 ISIS - Institut de Science et d'ingénierie supramoléculaires
2 LBCMCP - Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération
3 CRPP - Centre de Recherche Paul Pascal
4 SRSMC - Structure et Réactivité des Systèmes Moléculaires Complexes

A critical early step in drug discovery is the screening of a chemical library. Typically, promising compounds are identified in a primary screen and then more fully characterized in a dose-response analysis with 7-10 data points per compound. Here, we describe a robust microfluidic approach that increases the number of data points to approximately 10,000 per compound. The system exploits Taylor-Aris dispersion to create concentration gradients, which are then segmented into picoliter microreactors by droplet-based mi-crofluidics. The large number of data points results in IC 50 values that are highly precise (2.40% at 95% confidence) and highly reproducible (CV ˆ 2.45%, n ˆ 16). In addition, the high resolution of the data reveals complex dose-response relationships unam-biguously. We used this system to screen a chemical library of 704 compounds against protein tyrosine phosphatase 1B, a diabetes, obesity, and cancer target. We identified a number of novel inhi-bitors, the most potent being sodium cefsulodine, which has an IC 50 of 27 0.83 µM.

Domaines: Matière Condensée [cond-mat]; Sciences pharmaceutiques

Oliver Miller, Abdeslam El Harrak, Thomas Mangeat, Jean-Christophe Baret, Lucas Frenz, et al.. High-resolution dose-response screening using droplet-based microfluidics. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109, ⟨10.1073/pnas⟩. ⟨hal-02136487⟩