Molecular Libraries Probe Production

MLPCN Molecular Libraries Probe Production Centers Network... 

NIH MOLECULAR LIBRARIES PROBE PRODUCTION CENTERS NETWORK... 

Purpose The Molecular Libraries Roadmap offers public sector biomedical researchers access to the large-scale screening resources through the Molecular Libraries Probe Production Centers Network (MLPCN). The MLPCN has established a collection of 250,000 chemically diverse small... 

HTS is no longer limited to industrial settings and is starting to play an increasingly important role in academic research.112,113 With the new National Institutes of Health (NIH) initiatives in the USA to support a number of screening Molecular Libraries Probe Production Center Network (MLPCN) centres (http //ncgc.nih.gov/index.html) for academic research, it can be expected that the mutual impact of HTS and basic biology will increase. 

It is only in the past 5 years or so that chemical probe development has really taken off. This has largely been driven by the NIH roadmap initiative which engaged a network (Molecnlar Libraries Probe Production Centers Network http //mli.nih.gov/mli/ mlpcn/mlpcn/) of academic-based centers that provided state-of-the-art high-throughput screening (HTS) capabilities of a large diverse small-molecule library (the Molecular Libraries Small Molecule Repository (MLSMR) >350,000 compounds) as well as much expertise in the activities of assay development and downstream hit to probe (http //mli.nih.gov/mli/). Prior to this initiative, HTS was almost exclusively conducted within pharmacentical... 

The mass spectrometer should provide structural information that should be reproducible, interpretable and amenable to library matching. Ideally, an electron ionization (El) (see Chapter 3) spectrum should be generated. An interface that fulfils both this requirement and/or the production of molecular weight information, immediately lends itself to use as a more convenient alternative to the conventional solid-sample insertion probe of the mass spectrometer and some of the interfaces which have been developed have been used in this way. 

Scheme 1. Natural product (galanthamine) inspired compound library that led to the identification of a small molecular probe (denoted as secramine) to study a pathway that shuttles proteins from the endorplasmatic reticulum (ER) to the plasma membrane via the Golgi apparatus (GA).

Once a robust test assay has been set up, the choice of suitable compound libraries is the next key step. An excellent source of selective small molecule probes is the natural product pool. In an evolutionary process of millions of years, nature has come up with molecular structures that offer an evolutionary advantage to the species that makes the effort to synthesize these molecules. In most cases, these molecules are used to defend against enemies or to paralyze or kill preys. It is in the nature of these processes that such molecular weapons act most efficiently if they interfere with important biological processes of the target species, meaning that biologically relevant protein targets are addressed. 

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