The University of New Mexico Center for Molecular Discovery (UNMCMD), a specialty center focusing on multiplexed, HT flow cytometry, continues the New Mexico Molecular Libraries Screening Center (U54MH074425) and a Biomedical Research Partnership (R24EB000264). We invented the HT flow cytometry platform HyperCyt? and introduced it to the MLSCN. Our discovery tools enable homogeneous analysis of ligand binding and/or protein-protein interaction (PPI), multiparameter or high content analysis, and real-time measurements of cell response or binding. We analyze a 384 well plate in 11 min. Completed screens on the MLSMR have produced probes for cell (molecular and phenotypic) and bead-based targets. Experience indicates that most targets can be displayed in a flow cytometry compatible format. By creating a suspension array of particles, targets can be highly multiplexed or performed on complex cell populations without loss of throughput. Our team has produced >100 publications, >20 inventions, books on Flow Cytometry for Biotechnology and Virtual Screening, and >100 oral outreach presentations world-wide. We have >150 years of flow cytometry experience that includes applications in biochemistry, and cell and molecular biology compatible with a dual specialization in yeast targets. One of us has >20 years of experience in industrial HTS for >150 novel targets. We have core capabilities that include 1) effective outreach and partnership;2) identifying and developing innovative targets;3) implementing external primary and secondary assays;4) production mode screening of multiplexed targets;and 5) data upload to PubChem. We are uniquely positioned to integrate imaging agents and isotopes into the MLPCN. We intend to innovate in all of our activities. Through outreach, we will create and maintain a pipeline of multiplex assays for the MLPCN. Assay development will include, but not be limited to, yeast, eukaryotic, and profiling targets. We will create mechanisms to prioritize and implement partnerships for profiling targets and probes, including compound solubility, for the MLPCN. We will create tools to analyze and visualize multiplex HTS data sets. We will enhance and maintain collaborative tools for networking with target providers and Chemistry Specialty Centers for screening and follow up, and within the MLPCN for collaborative profiling and compound solubility. One Center Driven Project focuses on increasing throughput (from 384 to 1536 well format) and improving the performance of HT flow cytometry by exploiting recent design and engineering breakthroughs in our Center along with commercial partners. Through collaborative outreach, we will evaluate new discovery technologies emerging from the Los Alamos National Labs P41 National Flow Cytometry Resource. A second Center Driven Project develops a toolbox for yeast targets such as PPI, Pathway analysis, protein-DNA interactions, and a universal, multiplex yeast two-hybrid discovery platform.
Novel high throughput flow cytometry technology will be used for the discovery of small molecules that can serve as probes, imaging agents and leads in discovery for multiplexed biological targets. A pipeline of targets will developed through active outreach and consortium building efforts.
|Palsuledesai, Charuta C; Surviladze, Zurab; Waller, Anna et al. (2018) Activation of Rho Family GTPases by Small Molecules. ACS Chem Biol 13:1514-1524|
|Bredemeyer, Andrea L; Edwards, Bruce S; Haynes, Mark K et al. (2018) High-Throughput Screening Approach for Identifying Compounds That Inhibit Nonhomologous End Joining. SLAS Discov 23:624-633|
|Wu, Yang; Stauffer, Shaun R; Stanfield, Robyn L et al. (2016) Discovery of Small-Molecule Nonfluorescent Inhibitors of Fluorogen-Fluorogen Activating Protein Binding Pair. J Biomol Screen 21:74-87|
|Yang, Jeremy J; Ursu, Oleg; Lipinski, Christopher A et al. (2016) Badapple: promiscuity patterns from noisy evidence. J Cheminform 8:29|
|Zahoránszky-K?halmi, Gergely; Bologa, Cristian G; Oprea, Tudor I (2016) Impact of similarity threshold on the topology of molecular similarity networks and clustering outcomes. J Cheminform 8:16|
|Hong, Lin; Chavez, Stephanie; Smagley, Yelena et al. (2016) Relationship of light scatter change and Cdc42-regulated actin status. Cytometry B Clin Cytom 90:499-505|
|Sykes, David B; Kfoury, Youmna S; Mercier, François E et al. (2016) Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 167:171-186.e15|
|Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob et al. (2016) Targeting efflux pumps to overcome antifungal drug resistance. Future Med Chem 8:1485-501|
|Hong, Lin; Guo, Yuna; BasuRay, Soumik et al. (2015) A Pan-GTPase Inhibitor as a Molecular Probe. PLoS One 10:e0134317|
|Guo, Yuna; Kenney, S Ray; Muller, Carolyn Y et al. (2015) R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis. Mol Cancer Ther 14:2215-27|
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