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This version was published on September 1, 2007
Journal of Biomolecular Screening, Vol. 12, No. 6, 891-899 (2007)
DOI: 10.1177/1087057107302114
© 2007 Society for Biomolecular Sciences

Quality Control Procedures for Dose-Response Curve Generation Using Nanoliter Dispense Technologies

Catherine Quintero

Merck & Co., Inc., Merck Research Laboratories, Boston

Craig Rosenstein

Merck & Co., Inc., Merck Research Laboratories, Boston

Bethany Hughes

Merck & Co., Inc., Merck Research Laboratories, Boston

Richard Middleton

Merck & Co., Inc., Merck Research Laboratories, Boston

Ilona Kariv

Merck & Co., Inc., Merck Research Laboratories, Boston, Ilona_Kariv{at}Merck.com

With the advancement of high-throughput biomolecular screening techniques to the lead optimization stage, there is a critical need to quality control (QC) dose-response curves generated by robotic liquid handlers to ensure accurate affinity determinations. One challenge in evaluating the performance of liquid handlers is identifying and validating a robust method for testing dispense volumes across different instruments. Although traditional automated liquid handlers are still considered the standard platform in many laboratories, nanoliter dispensers are becoming more common and pose new challenges for routine quality control procedures. For example, standard gravimetric measurements are unreliable for testing the accuracy of nanoliter liquid dispenses. However, nanoliter dispensing technology allows for the conservation of compound, reduces compound carryover from well to well through discrete dispenses, and eliminates the need for intermediate compound dilution steps to achieve a low final DMSO assay concentration. Moreover, an intermediate dilution step in aqueous solution might result in compound precipitation at high concentrations. This study compared representative automation procedures done on a variety of liquid dispensers, including manual, traditional, and nanodispense volumes. The data confirmed the importance of establishing robust QC procedures for dose-response generation in addition to accuracy and precision determinations for each instrument, and they validated the use of nanoliter pipettors for dose-response testing. The results of this study also support the requirement for thorough mixing during serial compound dilutions prepared for high-throughput lead optimization strategies using traditional liquid handlers. (Journal of Biomolecular Screening 2007:891-899)

Key Words: nanoliter liquid handlers • discrete dispense • serial dilution • dose-response curve • lead optimization


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