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Improving Odds with Smarts: High-Throughput Methods for Screening Drug Candidates

Improving Odds with Smarts
Reported by
Jill U. Adams

Posted September 10, 2007


High-throughput screening for drug activity is a numbers game. It relies on how many compounds you can screen in an eight-hour work shift, or in a year. So far, however, a vastly increased screening capacity hasn't produced a corresponding increase in the number of likely drug candidates. Now, many scientists are looking for ways to increase the efficiency of the screening process—working smarter, not harder.

Four researchers presented their approaches to efficiency at a meeting of the Academy's Biochemical Pharmacology Discussion Group on April 24, 2007. The first two speakers, Jim Inglese and Matthew Sills, presented big-picture approaches to configuring libraries for compound identification in academia and industry. The final two speakers, Larry Sklar and Can Özbal, described the technological scaling up of previously low throughput methods—flow cytometry and mass spectrometry, respectively—each of which offer potential advantages over current high throughput assays.

Use the tabs above to find a meeting report and multimedia from this event.

Web Sites

Molecular Libraries Roadmap
The major components of the Molecular Libraries include the establishment of the Molecular Libraries Screening Centers Network (MLSCN), the Molecular Libraries Small Molecule Repository (MLSMR), a public Cheminformatics database (PubChem) and a series of technology development initiatives.

NIH Chemical Genomics Center
Provides information about the NCGC, how to work with the center, as well as useful assay development resources.

New Mexico Molecular Libraries Screening Center
Part of the NIH Molecular Libraries Initiative

PubChem provides information on the biological activities of small molecules. It is a component of NIH's Molecular Libraries Roadmap Initiative.

The Biomolecular and High Throughput Screening Information Portal
Comprehensive information on biomolecular screening and high throughput screening.

Journal Articles

Overview of the NIH Molecular Libraries Roadmap Initiative and the NCGC's Quantitative High Throughput Screening Approach to Chemical Genomics

Feng BY, Simeonov A, Jadhav A, et al. 2007. A high-throughput screen for aggregation-based inhibition in a large compound library. J. Med. Chem. 50: 2385-2390.

Inglese J, Auld DS, Jadhav A, et al. 2006. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc. Natl. Acad. Sci. USA 103: 11473-11478. FULL TEXT

Identification of Lead Compounds Using Different Screening Approaches in Lead Discovery

Sills MA, Weiss D, Pham Q, et al. 2002. Comparison of assay technologies for a tyrosine kinase assay generates different results in high throughput screening. J. Biomol. Screening 7: 191-214.

Wu X, Glickman JF, Bowen BR, Sills MA. 2003. Comparison of assay technologies for a nuclear receptor assay screen reveals differences in the sets of identified functional antagonists. J. Biomol. Screening 8: 381-394.

Integration of Virtual Screening with High-throughput Flow Cytometry to Identify Novel Small Molecules: Case Studies

Edwards BS, Bologa C, Young SM, et al. 2005. Integration of virtual screening with high-throughput flow cytometry to identify novel small molecule formylpeptide receptor antagonists. Mol. Pharmacol. 68: 1301-1310. FULL TEXT

Edwards BS, Young SM, Oprea TI, et al. 2006. Biomolecular screening of formylpeptide receptor ligands with a sensitive, quantitative, high-throughput flow cytometry platform. Nat. Protoc. 1: 59-66.

Simons PC, Young SM, Gibaja V, et al. 2007. Duplex, bead-based, competitive assays for inhibitors of protein kinase. Cytometry 7: 451-459.

Edwards BS, Young SM, Saunders MJ, et al. 2007. High-throughput flow cytometry for drug discovery. Expert Opin. Drug Discov. 2: 685-696.

High Throughput Screening via RapidFire™ Mass Spectrometry

Forbes CD, Toth JG, Özbal CC, et al. 2007. High-throughput mass spectrometry screening for inhibitors of phosphatidylserine decarboxylase. J. Biomol. Screen. [Epub ahead of print]

Özbal CC, LaMarr WA, Linton JR, et al. 2004. High throughput screening via mass spectrometry: a case study using acetylcholinesterase. Assay Drug Dev. Technol. 2: 373-381.


Jim Inglese, PhD

National Institute of Health
e-mail | web site | publications

Jim Inglese is deputy director of the NIH Chemical Genomics Center (NCGC), Bethesda, MD. The NCGC is an industrial-scale high-tech screening laboratory that functions within the Molecular Libraries Screening Center Network to discover small molecule modulators of cellular and biochemical processes. A veteran of the pharmaceutical and biotechnology industry, Inglese has developed a large number of assay methods and reagents. He is the author and inventor on over 80 scientific publications and patents, and the founding editor and editor-in-chief of the peer-reviewed journal, ASSAY and Drug Development Technologies.

Inglese earned his PhD in organic chemistry from the Pennsylvania State University and did his postdoctoral work with Robert J. Lefkowitz at Duke University. An industry veteran, Inglese has worked for both Pharmacopeia and Merck developing assays and technology for high-throughput screening, prior to joining the NIH.

Matthew Sills, PhD

Pharmacopeia Drug Discovery, Inc.
e-mail | web site | publications

Matthew Sills is executive director of preclinical development at Pharmacopeia, where he coordinates studies for toxicology and studies to nominatedevelopment candidates. He also leads several internal research projects. Prior to joining Pharmacopeia, Sills worked in drug discovery at the Novartis Institute for Biomedical Research in Summit, New Jersey, and has served as president of the Society for Biomolecular Sciences. His research interests are drug discovery and development, and addressing the question of why different screening results can be obtained when using different assay technologies.

Sills earned his PhD from the University of Pennsylvania in pharmacology and completed a postdoctoral fellowship at the NIH.

Larry A. Sklar, PhD

University of New Mexico
e-mail | web site | publications

Larry Sklar is Regents professor of pathology at the University of New Mexico in Albequerque, director of basic research at the UNM Cancer Center, and director of the New Mexico Molecular Libraries Screening Center, one of the ten screening centers funded by the NIH Molecular Libraries Roadmap. Sklar's research interests are signal transduction, cell adhesion, leukocyte biology, and high-throughput technologies for molecular assembly and drug discovery.

Sklar earned his PhD in chemistry at Stanford University and did postdoctoral work at the University of California at Santa Cruz and the Methodist Hospital in Houston, TX.

Can C. Özbal, PhD

Senior Director, BioTrove, Inc.
e-mail | web site | publications

Can "Jon" Özbal is a senior director and the business unit manager for RapidFire products at BioTrove, Inc. in Woburn, Massachusetts. Joining BioTrove as one of its first employees, he has worked on many aspects of the RapidFire platform, from designing and building the technology and its applications to managing collaborative research agreements with more than half of the top 12 largest pharmaceutical companies. His research interests lie in the area of the development and design of novel analytical instrumentation and methods.

Özbal earned his PhD from the Massachusetts Institute of Technology in Toxicology and was on the faculty at M.I.T. for two years before joining BioTrove.

Jill U. Adams

Jill U. Adams is a scientist-turned-science-writer based in Albany, New York.