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Since joining in September 2004 Dr. Auld has worked on establishing a center of scientific excellence that will serve the broader research community as a resource for assay optimization, high-throughput screening and chemical probe distribution. Research includes applying existing technologies to new protein families as well as exploring new assay detection technologies for unconventional target classes. This includes the use of miniaturized assay formats to improve the quality and information content that is obtained in high-throughput screening campaigns of chemical libraries. With this in mind the NCGC has developed a concentration-response-based screening approach termed quantitative HTS (qHTS) where compounds libraries (>100K in size) are rapidly screened at 7 or more concentrations. This has been applied to both biochemical and cell-based assays. Cell-based assays can exhibit complex concentration-response curves and many involve the simultaneous collection of multiple datasets. Part of his research includes establishing the formalism required to enumerate and mine the information present in such large concentration-response-based datasets (see Davis et al., 2007 below). Additionally, his laboratory is applying the qHTS format to enzyme families as well as evolutionarily related enzymes to investigate the chemical genomic map across families and species. Education of the research community on the methodologies of assay development and HTS is essential in making these resources widely accessible. Dr. Auld is involved with this educational initiative and has given lectures at John Hopkins University, served as chairman of the Education Committee for the Society of Biomolecular Sciences (SBS) since December 2004 and has worked with Eli Lilly scientist on developing the Assay Guidance Manual available on the NCGC web site.
Recent Publications:
- Auld DS, Inglese J, Jadhav A, Austin CP, Sittampalam GS, Montrose-Rafizadeh, Mcgee JE, Iverson PW. HTS technologies to facilitate chemical genomics. Eur. Pharm. Rev. 2007(2): 53-63.
- Davis RE, Zhang Y-Q, Southall N, Staudt LM, Austin C, Inglese J, Auld DS. A cellular assay for IkBa stabilization using a two-color dual luciferase-based sensor. Assays Drug Dev. Technologies 2007;5:85-103.
- Auld DS, Johnson RL, hang Y-Q, Veith H, Jadhav A, Yasgar A, Simeonov A, Zheng W, Martinez ED, Westwick JK, Austin CP, Inglese J. Fluorescent Protein-based cellular assays analyzed by laser scanning microplate cytometry in 1536-well plate format. Methods in Enzymol.:Measuring Biological Responses with Automated Microscopy. Vol 414. 2006 566-590.
- Inglese J, Auld DS, A, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative High-Throughput Screening (qHTS): A Titration-based Approach that Efficiently Identifies Biological Activities in Large Chemical Libraries. 2006 PNAS 103:11473-11478.
Prior to joing NCGC, Dr. Auld's experience is as follows:
- 1981-1985: B.S. in Biology from Gordon College Wenham, Mass. Synthesized protease substrates and angiogenic peptides using solid-phase synthesis.
Expertise: Biochemistry, peptide synthesis
- 1985-1989: Research Assistant, Harvard Medical School, Boston, Mass.
Isolation and characterization of human liver sorbitol dehydrogenase.
Laboratory of Prof. Bert L. Vallee
Expertise: Protein purification, enzymology
Selected publication:
- Maret, W. & Auld, D. S. (1988) Purification and chemical characterization of human liver soribitol dehydrogenase. Biochemistry 27, 1622-1628.
- 1989-1993: Ph. D. in Chemistry from the University of North Carolina at Chapel Hill, NC
Study the thermodynamics of protein folding using cytochrome c as a model system. Laboratory of Prof.Gary J. Pielak.
Expertise: Biophysics, 2D-NMR of proteins, molecular biology.
Selected publication:
- Auld, D. S. & Pielak, G. J. (1991) Constraints on amino acid substitutions in the N-terminal helix of cytochrome c. Biochemistry 30, 8684-8690.
- 1993-1996: Postdoctoral fellow within the Department of Biology at the Massachusetts Institute of Technology, Cambridge, Mass. Research focused on protein-RNA interactions and mechanisms that define the genetic code.
Laboratory of Prof. Paul Schimmel
Expertise: structure/function of tRNA synthetases. Developed binary codon mutagenesis.
Selected publication:
- Auld, D. S. & Schimmel, P. (1995) Single amino acid swap in a transplanted peptide switches anticodon recognition of two tRNA-synthetases. Science 267, 1994-1996.
- 1996-2004: Pharmacopeia, Inc. Cranbury, NJ.. Assistant Director of Drug Discovery, Discovered novel inhibitors for human iNOS, lead the biology effort of internal and international programs in drug discovery.
Expertise: Assay Development; High-throughput screening; Lead Optimization and pre-clinical research within several programs covering multiple targets including GPCRs, protein kinases and nuclear receptors. This effort encompassed several therapeutic areas that included inflammation, depression and pain and contributed to clinical candidates.
Selected publications:
- Brescia M-R, Rokosz LL, Cole AG, Stauffer TM, Lehrach JM, Auld DS, Henderson I, Webb ML. Discovery and preliminary evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin receptor antagonists Bioorganic & Medicinal Chemistry Letters 2007;17: 1211-1215.
- Ho, K-K, Auld, DS, Bohnstedt, AC, Conti, P, Dokter, W, Erickson, S, Feng, D, Inglese, J, Kingsbury, C, Kultgen, SG, Liu, R-Q, Masterson, CM.; Ohlmeyer, M, Rong, Y, Rooseboom, M, Roughton, A, Samama, P, Smit, M-J, Son, E, Van der Louw, J, Vogel, G, Webb, ML, Wijkmans, J, You, M.. Imidazolylpyrimidine based CXCR2 chemokine receptor antagonists. Bioorganic & Medicinal Chemistry Letters 2006;16: 2724-2728.
- McMillan K, Adler M, Auld DS, Baldwin JJ, Blasko E, Browne LJ, Chelsky D, Davey D, Dolle RE,. Eagen KA, Erickson S, Feldman RI, Glaser CB, Mallari C, Morrissey MM, Ohlmeyer MHJ, Pan G, Parkinson JF, Phillips GB, Polokoff MA, Sigal NH, Vergona R, Whitlow M, Young TA, and Devlin JJ. (2000) Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. PNAS 97, 1506-1511.
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