Molecular Library and Imaging Francis Collins, NHGRI Tom Insel, NIMH Rod Pettigrew, NIBIB

Building Blocks and PathwaysFrancis Collins,NHGRI Richard Hodes, NIAT-K Li, NIAAA Allen Spiegel, NIDDK

Structural Biology Jeremy Berg, NIGMS Paul Sieving, NEI

Bioinformatics and Computational BiologyJeremy Berg, NIGMS Don Lindberg, NLM

Nanomedicine Jeffery Schloss, NHGRI Paul Sieving, NEI

NEW PATHWAYS TO DISCOVERYWorking Group and Co-Chairs

Francis S. Collins, M.D., Ph.D.

New Pathways to Discovery:The Molecular Libraries and Imaging Roadmap Initiative

New Pathways to Discovery 

Molecular Libraries and Imaging

Building Blocks, Biological Pathways and Networks

Structural Biology

Bioinformatics and Computational Biology

Nanomedicine

Four recent developments makesmall molecules/chemical genomics

initiative possible

Combinatorial Chemistry

Robotic TechnologyHGP

Availability of targets

Availability of screening

Availability of compounds

Public sector screening and chemistry initiative

CompoundAvailability

Molecular Libraries:Putting Chemistry to Work for

Medicine Six national screening centers for small

molecules Public database for “chemical genomics” Technology advances in combinatorial

chemistry, robotics, virtual screening

Collaborative Pipeline of a NIH Chemical Genomics Center

Investigator

Customized Assay

Screen

Probe picking, confirmation, secondary

screens

Probe List

Limited MedChem

Compound Repository

Cheminformatics, PubChem

(NCBI)

Assay

Peer review

Small Molecule Repository Contract award in 2004

Screening Centers Intramural center: operational in 2004 Extramural centers: Request for Information issued

11/21/03o received responses from universities and a few small

biotechnology companies RFA release in Mar., receipt date summer, awards in spring

2005 Coordinating center for repository and screening centers

o Contract award in 2005

Molecular Libraries Repository & Screening Centers

Molecular Imaging Roadmap Components

Development of high resolution probes for cellular imaging RFA issued in 2004 http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-

001.html Development of an imaging probe database

In process, with links to PubChem Core synthesis facility to produce imaging probes

Efforts to establish an intramural facility are underway

Potential Outcomes of Molecular Libraries & Imaging Probes Activities

Development of research tools (molecular probes and novel assays) to facilitate studies of biology and pathophysiology

Advances in biological research leading to the identification and validation of novel biological targets for therapeutics development

Discovery of biological markers to monitor disease progression and to predict treatment response

Structural Biology, Bioinformatics, Computational Biology

and Nanomedicine

Jeremy M. Berg, Ph.D.

Structural Biology

Initiative: Centers for Innovation in Membrane Protein Production

Applications due March 11, 2004 $5M FY2004 Roadmap funding (~2 Centers,

P50 Mechanism)

Centers for Innovation in Membrane Protein Production

Many physiologically and pharmaceutically important proteins are membrane proteins

Few membrane proteins structures known All eukaryotic membrane protein structures

determined to date have been from proteins derived from naturally rich sources

Detergents and other agents required for solubilization and crystallization

Development of methods for the production of structurally and functionally intact membrane proteins for subsequent structural studies

0

2

4

6

8

10

12

14

16

1960 1970 1980 1990 2000

nu

mb

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of s

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res

year

water-soluble proteins

membrane proteins

progress in membrane protein structure determinations parallels that of water-soluble proteins with a ~25 year offset

B.W. Matthews Ann. Rev. Phys. Chem. 27, 493 (1976)

http://www.mpibp-frankfurt.pg.de/michel/public/memprotstruct.html

Courtesy of Doug Rees, Caltech

Structural Biology Roadmap Plans

Wide range of structural biology programs throughout NIH (intramural and extramural)

Synchrotron sources (NCRR, NCI, NIGMS) and NMR instrumentation (NCRR, NIGMS) supported

Protein Structure Initiative-Network of Centers devoted to structural genomics

Roadmap initiatives will be used to provide integration of these programs

Bioinformatics and Computational Biology

Initiative: National Centers for Biomedical Computing

Applications received January 23, 2004 $12M FY2004 Roadmap funding (~4

Centers, U54 Mechanism)

National Centers for Biomedical Computing

Partnerships of: Computer scientists Biomedical computational scientists Experimental and clinical biomedical and behavioral

researchers Focused on software rather than hardware Each National Center to have Driving Biological

Projects Open source requirement Programs in preparation for partnerships between

individual investigators and National Centers

Nanomedicine Roadmap Initiative

Nanomedicine describes the interface of biology and nanotechnology to understand and treat disease.

Nanomedicine is a departure from the majority of nanotechnology research in that it integrates biomolecular processes toward developing therapies.

Will need to develop new tools and a nanomedicine lexicon for shared use by engineers and biologists.

Next Steps: Concept Development Awards in ’04; solicitation for Nanomedicine Development Centers in ‘05

2/2004