We have developed innovative flow cytometric tools for discovery research that enable homogeneous analysis of ligand binding and protein-protein interaction, HT sample handling, high content analysis, and real-time measurements of cell response. We have already achieved delivery rates of ?l sized samples from multiwell plates at rates up to 100 samples/min end point assays and multiplex rates up to 1000/min. We have completed screens on several small molecule libraries, discovering novel small molecules that bind to a GPCR peptide receptor. Our experience indicates that virtually any molecular assembly or cell response can be displayed in a format compatible with flow cytometry. Moreover, by creating a suspension array of particles, assays and responses can be highly multiplexed or performed on complex cell populations without loss of throughput. Our novel sampling approach (HyperCyt(r)) makes flow cytometry an attractive platform for drug discovery, proteomics, and real-time analysis of molecular interactions. Flow cytometry is particularly convenient for alternately assessing both cellular and molecular activities of small molecules. To our knowledge, there is no single competing technology that offers the versatility of flow cytometry for Molecular Library Initiative screening or that has the potential of being available to such a large number of laboratories that house flow cytometers (20,000 world-wide). Our team brings together expertise that spans biomedical, biophysical, chemical, computational, instrumentation and engineering disciplines. The team represents an established group already working together through 1R24EB00264, a BRP previously funded to develop high throughput flow cytometry. The BRP is currently applied to our own targets in GPCR signaling pathways. Our screening center will be composed of three scientific teams (Core 1, Assay Optimization; Core 2, Screening and Automation; Core 3, Cheminformatics and Chemistry) and an Integrating core lead by PI, Larry Sklar, who will oversee the Center. Core 1, led by Co-PI Eric Prossnitz, will optimize NIH target assays for high throughput flow cytometry. Core 2, led by Co-PIs Bruce Edwards and ? Herbert Tanner will perform HT screens and automate the flow cytometry platform. Core 3, led by Co-PIs Tudor Oprea and Jeffrey Arterburn will integrate cheminformatics and synthetic chemistry teams to increase the overall efficiency of the discovery process. ? ?
| 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 |
| Yang, Jeremy J; Ursu, Oleg; Lipinski, Christopher A et al. (2016) Badapple: promiscuity patterns from noisy evidence. J Cheminform 8:29 |
| 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 |
| Agola, Jacob O; Sivalingam, Daniel; Cimino, Daniel F et al. (2015) Quantitative bead-based flow cytometry for assaying Rab7 GTPase interaction with the Rab-interacting lysosomal protein (RILP) effector protein. Methods Mol Biol 1298:331-54 |
| Chigaev, Alexandre; Smagley, Yelena; Haynes, Mark K et al. (2015) FRET detection of lymphocyte function-associated antigen-1 conformational extension. Mol Biol Cell 26:43-54 |
| Oprea, Tudor I; Sklar, Larry A; Agola, Jacob O et al. (2015) Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases. PLoS One 10:e0142182 |
| 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 |
| Guo, Yuna; Kenney, S Ray; Cook, Linda et al. (2015) A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients. Clin Cancer Res 21:5064-72 |
| Edwards, Bruce S; Sklar, Larry A (2015) Flow Cytometry: Impact on Early Drug Discovery. J Biomol Screen 20:689-707 |
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