UCSF Small Molecule Discovery Center: Innovation, Collaboration and Chemical Biology in the Bay Area

Abstract

The Small Molecule Discovery Center (SMDC) at the University of California, San Francisco, works collaboratively with the scientific community to solve challenging problems in chemical biology and drug discovery. The SMDC includes a high throughput screening facility, medicinal chemistry, and research labs focused on fundamental problems in biochemistry and targeted drug delivery. Here, we outline our HTS program and provide examples of chemical tools developed through SMDC collaborations. We have an active research program in developing quantitative cell-based screens for primary cells and whole organisms; here, we describe whole-organism screens to find drugs against parasites that cause neglected tropical diseases. We are also very interested in target-based approaches for so-called "undruggable", protein classes and fragment-based lead discovery. This expertise has led to several pharmaceutical collaborations; additionally, the SMDC works with start-up companies to enable their early-stage research. The SMDC, located in the biotech-focused Mission Bay neighborhood in San Francisco, is a hub for innovative small-molecule discovery research at UCSF.

A Liquid Chromatography/Mass Spectrometry Method for Screening Disulfide Tethering Fragments

“…The outputs from equations (1) and (2) were then loaded into the SMDC’s MySQL database for further analysis in a custom web application, HiTS. 22…”

“…The outputs from equations (1) and (2) were then loaded into the SMDC's MySQL database for further analysis in a custom web application, HiTS. 22 In conclusion, we report an optimized LC/MS method for screening intact protein for covalent adduct formation, using a library of disulfide-capped fragments. By taking advantage of advances in UPLC and ESI-TOF technology, we have developed an LC method capable of more rapid (<90 s) and sustainable injections than previously reported.…”

Kinase Atlas: Druggability Analysis of Potential Allosteric Sites in Kinases

“…Nevertheless, the study discovered a variety of small-molecule fragment disulfides that could either activate or inhibit PDK1 by conjugation to the PIF pocket . Considering the success of this and a variety of other applications, the tethering method remains an important tool in the UCSF Small Molecule Discovery Center …”

“…68 Considering the success of this and a variety of other applications, the tethering method remains an important tool in the UCSF Small Molecule Discovery Center. 69 Screening for fragment binding to CDK2 was performed by monitoring mixed disulfide formation between the protein and the fragment using intact protein mass spectrometry on a Waters LCT Premier (LC-TOF) with in-line C4 desalting column (Figure S4). Each tethering reaction was run in Tris-buffered saline containing 2 μM CDK2, 100 μM of a small-molecule disulfide, and 1 mM βME as a reductant.…”

Microbial metal resistance and metabolism across dynamic landscapes: high-throughput environmental microbiology

“…Thus, only by altering the concentrations of multiple inorganic or organic compounds in a massively parallel, high-throughput cultivation platform can we gain a quantitative bottom-up picture of gene-microbe-metabolism-environment interactions. Several high-throughput approaches developed in the biomedical sciences can be applied to problems in environmental microbiology, including high-throughput screens to identify inhibitory compounds, dose-response microplate assays to quantify the inhibitory potency of compounds, checkerboard synergy assays to evaluate non-linear interactions between compounds, and leave-one-out assays to evaluate formulation potencies 8, 15 . However, most of the compounds used in the biomedical industry (for example, drugs) are not environmentally relevant.…”