Biomedical Engineering Reference
In-Depth Information
structures or pathways potentially serving as imaging agents or leads for drug
discovery. Data were to be promptly uploaded to the public database [10]. The
pilot-phase centers used both commercial and home-grown screening technologies,
including high-throughput flow cytometry.
Questions immediately arose regarding the role of NIH in HTS and discovery,
previously the domain of the pharmaceutical industry [11]. In brief, these questions
included (1) the cost-benefit of the initiative; (2) whether NIHwas in competition with
the pharmaceutical industry; (3) how the infrastructure could be developed for
acquiring and managing the compound library, as well as for data publication, and
so on; and (4) the nature of the conflict between public data and commercial value.
A summary of the probe output of the pilot phase has appeared [12].
It is noteworthy that the period of 2000-2010 marked significant changes in
the pharmaceutical industry itself: (1) a plateau in the pipeline of new chemical
entities reaching approval as new drugs; (2) downsizing and mergers contributing to
job loss in the discovery sector and medicinal chemistry enterprises; (3) outsourcing
these activities to Russia, China, and India; and (4) significant growth in discovery
activities in academic as well as freestanding research institutions. There are listings
of 66 sites in Society for Biomolecular Sciences Academic Screening Center
Directory [13].
Now in the production phase, there are four comprehensive centers in the
Molecular Libraries Probe Production Center Network (TSRI, SBIMR, Broad
Institute, and National Chemical Genomics Center), three specialty screening centers
(UNM, Southern Research Institute, and Johns Hopkins University), and two speci-
alty chemistry centers (University of Kansas and Vanderbilt University). The goal of
the MLPCN is to complete screens on 100 targets per year over a 6 year period with a
library of
300 probes as well as a comparison of
the activities of the library against all the targets in the public database is projected.
The University of New Mexico Center for Molecular Discovery (UNMCMD),
specializing in HTS flow cytometry, has identified 10 probes so far and uploaded
more than 6M screening data points.
As of January 2010, there are several funding mechanisms for discovery projects
that are open to investigators throughout the world. The R03 mechanism [14] is for
targets that are ready for screening. The funding provides a means for investigators to
participate along side the screening center. The R21 mechanism [15] is for the
development of targets to be screened, with resources in the first year for reducing the
target to practice in a multiwell screening format. The second year of funding is for
partnering with MLPCN centers during the screening and follow-up phases of the
project. Individual investigators can be funded by R01 mechanisms that have small-
molecule discovery and HTS components. The program announcements change
frequently and can be readily assessed through web searches. However, the MLPCN
also provides a mechanism for investigators developing HTS targets to enter the
MLPCN through a Fast Track mechanism [16] as well as progressing the R21 to
screening [17]. Funding opportunities are summarized [18].
As a public initiative, the HTS and follow-up studies for the MLPCN are compiled
into a searchable database, PubChem, which allows searches of targets and detailed
350,000 compounds. An output of
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