We are requesting funds to purchase a high throughput surface plasmon resonance instrument (HT-SPR). This instrument will be used to identify and characterize small molecules that bind to biological targets of interest. These compounds will then serve as starting points for development of molecular probes and drug leads. There are no HT-SPR instruments at UCSF or nearby campuses. The Mission Bay campus has a Biacore T100 which is highly valued and heavily used. However, it does not have the appropriate throughput for routine screening. The addition of an HT-SPR would therefore serve a unique purpose at UCSF. The new equipment would be placed in the Small Molecule Discovery Center (SMDC) at UCSF and be available to the entire UC community. The SMDC has already established the space, staff, and recharge policies to maintain this equipment. The SMDC includes a high-throughput screening (HTS) group and is therefore well-positioned to maximize the use of new compound-discovery technology. HTS is a key tool for identifying compounds with new biological activities and involves assaying many thousands of compounds in parallel against a target of interest. To achieve such throughput, most assays measure changes in function. There are, however, many challenging targets for which it would be advantageous to select compounds for binding in the initial screen. For example, fragment-based compound discovery focuses on low molecular weight, low affinity compounds. Binding methods, such as SPR, NMR, and x-ray crystallography, have been much more successful than activity-based assays in selecting high- quality fragments. We have been applying such approaches to challenging targets for several years, and are very excited by the new HT-SPR technologies that are available. SPR is one of the most sensitive and information-rich methods for monitoring binding but, until recently, no high-throughput instruments were available. SPR detects, in real time, the binding of analytes to biomolecules immobilized on a surface. From these traces, one can derive binding affinity, stoichiometry, and kinetics. Very recently, a number of companies have introduced HT-SPR instruments with the ability to measure up to 3500 binding interactions in a day. Two of the instruments most relevant to small-molecule screening are the AP3000 (Fujifilm) and the A100 (Biacore). These instruments represent the state-of-the-art in high throughput binding measurements, and are enabling a new paradigm for HTS. The SMDC has served as a beta test site for the AP3000, and we have decided to purchase this instrument for small-molecule screening. The purchase of this instrument has broad support;the major and minor users listed in this proposal come from six departments at two different campuses, and their research interests involve new drug discovery technologies and developing therapies in a variety of disease areas. The HT-SPR instrument will facilitate the NIH-funded research of these users and future minor users throughout UCSF.
The AP3000 (Fujifilm) HT-SPR instrument that we are requesting funds for represents a new, highly sensitive and rapid method for identifying compounds with new biological activity. These compounds can be used to elucidate basic biological mechanisms and/or as leads for new therapeutics for a wide variety of human diseases.
