Molecular Libraries and Imaging

Small molecules, often with molecular weights of 500 or below, are extremely important for researchers to explore function at the molecular, cellular, and in vivo level. Such molecules have also proven valuable for treating diseases, and most medicines marketed today are from this class.

The Molecular Libraries Program offered public sector biomedical researchers access to the large-scale screening capacity necessary to identify small molecules that could be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. This led to new ways to explore the functions of genes and signaling pathways in health and disease.

NIH anticipated that these projects would also facilitate the development of new drugs, by providing early stage chemical compounds to researchers in the public and private sectors for validation of new drug targets, which could then be moved into the drug-development pipeline. This model of drug development may be particularly useful for rare diseases and areas of unmet medical need, which may not be attractive for development by the private sector.

Three key technological advances drove NIH's effort to build small molecule libraries. First, the successful completion of the Human Genome Project provided an enormous amount of human biology to be studied and innumerable potential drug targets to be discovered. Second, developments in chemistry gave researchers in the public sector the ability to rapidly and efficiently synthesize large numbers of related molecules, a capability previously available only to researchers in pharmaceutical and biotechnology companies. Third, advances in robotic technology and informatics allowed scientists to screen hundreds of thousands of compounds in a single day, a screening capacity that is orders of magnitude greater than a decade ago.

The Molecular Libraries Program had three components:

1. Molecular Libraries Probe Production Centers Network (MLPCN). This nationwide consortium of small molecule screening centers was funded to produce innovative chemical tools for use in biological research. The MLPCN performed HTS on assays provided by the research community, against a large library of small molecules maintained in a central molecule repository. The network also performed optimization chemistry required to produce useful in vitro chemical probes (research tools for the targets or phenotypes studied in the assays) from the “hits” identified in the initial screening. The MLPCN established a collection of over 350,000 chemically diverse small molecules  some of which have known biological activities and others of which have the potential to modulate novel biological functions. This collection will continue to be expanded and modified to provide a working set of molecules that will target larger domains of "biological space," which represents all of the biomolecular surface domains that can potentially interact with a small molecule. All of the results from the MLPCN’s activities were placed into a public database called PubChem, and information about probe compounds was made available to all researchers, in both public and private sectors, for their use in studying biology and disease.
2. PubChem. A comprehensive database of chemical structures and their biological activities was developed by the National Center for Biotechnology Information at NIH. PubChem houses both compound information from the scientific literature as well as screening and probe data from the MLPCN.
3. Technology Development.  The ultimate goal of the Molecular Libraries Program was to develop a comprehensive set of small molecule modulators for the majority of the genes and functions of humans and other organisms. Therefore, the Molecular Libraries Program was devoted to technology development in the following three areas:
    
   • Chemical Diversity. This area supported the development of new and diverse chemical libraries for screening in the MLPCN centers, as well as new methods for producing, isolating, characterizing, and modifying natural products.
      
   • Assay diversity. This area supported the development of a continuously evolving stream of scientifically novel and technologically outstanding assays that could be automated and used for screening small molecules within the Molecular Libraries Probe Production Centers Network. The aim of this effort was to enable the design of pharmacologic tools to explore cellular and physiological function.
      
   • Instrumentation. This area supported the development of new methods for high-throughput measurement of novel biological assays.

The Molecular Libraries Program also enhanced the discovery and availability of small molecules for molecular imaging, including imaging of molecules or molecular events in biological systems that spanned the scale from single cells to whole organisms. Ultimately, it is hoped that this effort will enable personalized profiles of cell and tissue function, which may lead to more individualized approaches to diagnosing and treating disease. By significantly enhancing the support of this field, NIH ensured that molecular imaging became a powerful tool for biomedical research and will continue to be a synergistic component of research in molecular medicine that promises landmark improvements in clinical care.

• Molecular Imaging and Contrast Agent Database (MICAD). This database catalogs imaging probe information, describing the specificities, activities, and applications of imaging probes for a wide range of diseases and biological functions.
   
• Imaging Probe Development Center (IPDC). This center, which is now part of the intramural program of the National Heart, Lung and Blood Institute (NHLBI), offers the production of known imaging probes for the research community in cases where there is no viable commercial supplier, and generates novel imaging probes for biomedical research and clinical applications.

For more information on the Molecular Libraries Program contact Carson Loomis Senior Advisor to Institute Director National Center for Advancing Translational Sciences (NCATS) at loomisc@mail.nih.gov.