title: A robotic platform for quantitative high-throughput screening.
abstract: High-throughput screening (HTS) is increasingly being adopted in academic institutions, where the decoupling of screening and drug development has led to unique challenges, as well as novel uses of instrumentation, assay formulations, and software tools. Advances in technology have made automated unattended screening in the 1,536-well plate format broadly accessible and have further facilitated the exploration of new technologies and approaches to screening. A case in point is our recently developed quantitative HTS (qHTS) paradigm, which tests each library compound at multiple concentrations to construct concentration-response curves (CRCs) generating a comprehensive data set for each assay. The practical implementation of qHTS for cell-based and biochemical assays across libraries of > 100,000 compounds (e.g., between 700,000 and 2,000,000 sample wells tested) requires maximal efficiency and miniaturization and the ability to easily accommodate many different assay formats and screening protocols. Here, we describe the design and utilization of a fully integrated and automated screening system for qHTS at the National Institutes of Health's Chemical Genomics Center. We report system productivity, reliability, and flexibility, as well as modifications made to increase throughput, add additional capabilities, and address limitations. The combination of this system and qHTS has led to the generation of over 6 million CRCs from > 120 assays in the last 3 years and is a technology that can be widely implemented to increase efficiency of screening and lead generation.
authors.affiliation: NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20850, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Michael
authors.forename: Douglas
authors.initials: D
authors.lastname: Auld
authors.forename: Carleen
authors.initials: C
authors.lastname: Klumpp
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Natasha
authors.initials: N
authors.lastname: Thorne
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: James
authors.initials: J
authors.lastname: Inglese
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
mesh_terms: D018929:Cell Culture Techniques / Q000295:instrumentation; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation*; D004868:Equipment Failure; D047569:Laser Scanning Cytometry; D015203:Reproducibility of Results; D012371:Robotics