Southern Research Institute
A Molecular Libraries Screening Center Program
- The Southern Research Molecular Libraries Screening Center Team
- Fig. 1: Distribution of SRMLSC Assays by Type
- Fig 2: Total Number of Compounds Screened by the SRMLSC. Descriptions of the individual assays and the results are available on PubChem (http://pubchem.ncbi.nlm.nih.gov/).
- Table 1: A Selection of Scaffolds Entering Probe Optimisation Chemistry
A goal of the NIH Roadmap Initiative is to empower the scientific community with small molecule probes to study biological processes involved in health and disease. Since 2005, the Southern Research Molecular Libraries Screening Center (SRMLSC) has conducted over 30 HTS campaigns and has uploaded nearly 4 million data points to PubChem. Given that most assays conducted by the MLSCN involve non-conventional drug targets, this program is anticipated to result in a rich and unique database of compounds for investigators with interests in drug discovery.
For more than 65 years, Southern Research Institute has been one of the leaders in the fields of drug discovery and drug development. The primary goal of its pharmacological research is to identify novel, small molecule compounds and progress these lead compounds from discovery to FDA acceptance. SRI is concerned with the discovery of anti-cancer agents having discovered six FDA-approved treatments with an additional six drug leads currently in clinical trials. Additional therapeutic discovery work is being done in infectious diseases and in neuroscience. Three major groups in the company's drug discovery division have led the way to its success: medicinal chemistry, biochemistry and molecular biology, and high-throughput screening.
As a not-for-profit entity, SRI's drug discovery research is often supported by funding from the National Institute of Health and other government organisations. Even as the government funding is granted to a particular department or group, the three departments have all contributed to the achievements of Southern Research's drug discovery efforts in multiple contracts or projects. Following the success in screening hundreds of thousands of compounds through these NIH-funded programs, SRI was again recognised for its outstanding drug discovery accomplishments and chosen to be a screening center as part of the Molecular Libraries Screening Centers Network (MLSCN). In June of 2005 the Southern Research Molecular Libraries Screening Center (SRMLSC) was created.
The SRMLSC has had a total of thirty-four assays assigned to it through this program, more than any other extramural center in the network.
A further break-down of the assays by type is highlighted in figure 1 demonstrating the SRMLSC's ability to fulfill one aim of the MLSCN: to carry out a broad range of biochemical and cellular-based assays. The assignments originated from an assortment of academic organisations with varying fields of expertise. The staff's depth of knowledge was tested and proven during the implementation of each of these projects. Moreover, our staff also submitted their own assays to the network thus meeting another objective of the program: the development of innovative assays for compound screening. The quality of data produced by these screening endeavors has led to the medicinal chemistry group's work on probe development projects on 15 chemical scaffolds identifying approximately seventy compounds thus meeting another important goal of the MLSCN (table 1).
The construction and assembly of the high-throughput screening center at Southern Research several years before the establishment of the SRMLSC was an advantage to the program. Removing the lag time for equipment purchase, employee training, and proper operation, the group moved the assigned assays from validation phase to screening on the robotics platforms. As the center had already shifted most of its screening campaigns to 384-well format, increased production as a required goal of the MLSCN to screen compounds in a higher density 1536-well format was achieved in several different types of assays. To aid in the efficiency of this process one key piece of equipment, an acoustic-based liquid handling dispenser, was integrated into the existing HTS operations. As a means of monitoring the quality of the data produced by the SRMLSC, a Laboratory Information Management System (LIMS) was also incorporated into the screening set-up to capture information on all constituents that could affect the outcome of a screen. Every part of the screening process, from reagents to consumables to instrumentation including QC measurements, is stored in this database for querying. Additionally the SRMLSC Informatics team used ActivityBase for collecting compound library samples' molecular structures and storing each samples' associated screening data. In addition to the capabilities mentioned above, a specialised service that the SRMLSC contributed to the network is the capacity to screen in BSL-2/3 containment. The BSL-2 and BSL-3 facilities were used in several screening projects already established by SRI's drug discovery group. The group adapted incoming MLSCN assays requiring BSL-2 or BSL-3 level containment to the existing screening system.
The success of the SRMLSC as part of the NIH's Molecular Libraries Screening Center Network can be attributed to Southern Research's proven track record in the field of drug discovery along with the dedication and depth of expertise of the personnel. Figure 2 shows not only the overall number of compounds screened by Southern Research over the course of the project (3,734,389) but also how the production and efficiency of the SRMLSC continues to improve and evolve.
This work was funded by NIH Molecular Libraries Screening Center Network, Contract 1 U54 HG003917-002 (G.A.P). Over the three years covered by this grant many individuals have contributed to the success of the SRMLSC.