Compound Libraries

Investigators have access to the UT Southwestern chemical library, which consists of 300,000 small molecules from commercial sources, 2,500 compounds from UT Southwestern chemists, and about 7,100 partially purified natural product fractions (each natural product fraction contains 3-10 natural products). The HTS laboratory has multiple copies of the institutional library, which is dissolved in DMSO and arrayed in 384-well plates.

The commercial compounds were purchased from major suppliers to the pharmaceutical industry. These compounds passed 48 structure-based filters that identified undesirable characteristics as well as satisfied a relaxed set of Lipinski's rules for good bioavailability. Those that were purchased represented the desirable structural diversity available from the following companies: ChemDiv (150,000 compounds), ChemBridge (125,500), ComGenex (22,000), Prestwick Chemical, (1,100) and TimTec (500).

Professor John MacMillan, Ph.D., a natural products chemist at UC Santa Cruz, provides the marine natural product fraction collection. As a principal investigator with expertise in natural product chemistry and isolation methods, Dr. MacMillan has established a "preparative pipeline" for a natural product screening collection that currently contains approximately 7,360 natural product fractions from a diverse group of marine-derived actinomycetes, Firmicutes, and Proteobacteria, the majority of which come from the Gulf of Mexico (Texas, Florida, and Louisiana) and the rich estuary system of South Carolina.

He has cultured these bacteria using a specialized "toolbox" of small-molecule signaling compounds (e.g., N-acyl homoserine lactones, siderophores, surfactins, etc.) that, in appropriate combination and concentration, can mimic the natural environment of each bacterial strain. These strains represent an affordable and renewable resupply of natural products of interest derived from these sources.

The diversity of the bacterial collection and the associated natural products is considerable, with the former containing representatives from the order of Actinomycetales (10 different families) as well as strains from genera Gordonia (Corynebacteriaceae), Frankia, the alphaproteobacteria Erythrobacter (non-actinomycete strains), and bacilli.

The chemistry of the natural products isolated from these bacteria has proved diverse with respect to structural classes (e.g., polyketides, alkaloids, terpenes, and hybrid-structures). As would be expected, the natural products library contains novel compounds as well as those that have been previously characterized.

Genomic siRNA Libraries

The HTS Core manages a human genomic library from Dharmacon as well as C. elegans and Drosophila genomic RNAi libraries from Ambion that were purchased by UT Southwestern. These libraries are available to UT Southwestern investigators who propose experiments acceptable to an oversight committee (contact Bruce Posner, Ph.D., for details, Email).

The human genomic library is composed of pools of four double-stranded siRNA oligos specific for each of 21,125 human genes arrayed in 96-well plates. All libraries are kept in multiple copies in -80°C or -20°C freezers within the 3,900-square-feet in the HTS laboratories.