Shoichet Laboratory

Lab members

Brian K. Shoichet, Ph. D.
Professor

Brian
Short biosketch

video: Shoichet, channeling William F. Buckley, offers a vigorous defense of docking and high-throughput screening for the graduate student retreat (interviewedby Emily Crawford, channeling Steven Colbert).

podcast: Shoichet, in a public interview, tries desperately to sound less confused than he actually is.

Recent reviews, book chapters, and papers:

  • Shoichet BK. Screening in a spirit haunted world. Drug Discov Today 11 (13-14), 607-15 (2006). [Pubmed | DOI | Download PDF]
  • Shoichet BK. Interpreting Steep Dose-Response Curves in Early Inhibitor Discovery. J Med Chem 49 (25), 7274-7277 (2006). [Pubmed | DOI | Download PDF]

Sarah Boyce
CCB Graduate student

I'm working with new model binding sites in cytochrome c peroxidase to investigate and improve the DOCK scoring function, specifically with an interest in receptor desolvation.

Sarah

Publications:

  • Graves AP, Shivakumar DM, Boyce SE, Jacobson MP, Case DA, Shoichet BK. Rescoring docking hit lists for model cavity sites: predictions and experimental testing. J Mol Biol 377 (3), 914-34 (2008). [Pubmed | DOI | Download PDF]
  • Brenk R, Vetter SW, Boyce SE, Goodin DB, Shoichet BK. Probing molecular docking in a charged model binding site. J Mol Biol 357 (5), 1449-70 (2006). [Pubmed | DOI | Download PDF]

Yu Chen, Ph. D.
Postdoc

Studying beta-lactamase function and inhibition through ultrahigh resolution X-ray crystallography and molecular docking.

Publications:

  • Chen Y, McReynolds A, Shoichet BK. Re-examining the role of Lys67 in class C beta-lactamase catalysis.. Protein Sci 18 (3), 662-9 (2009). [Pubmed | DOI]
  • Chen Y, Shoichet BK. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nature Chemical Biology 5 (5), 358-364 (2009). [Pubmed | DOI | News and Views | Download PDF]
  • Delmas J, Chen Y, Prati F, Robin F, Shoichet BK, Bonnet R. Structure and dynamics of CTX-M enzymes reveal insights into substrate accommodation by extended-spectrum beta-lactamases. J Mol Biol 375 (1), 192-201 (2008). [Pubmed | DOI | Download PDF]
  • Whiteson KL, Chen Y, Chopra N, Raymond AC, Rice PA. Identification of a potential general acid/base in the reversible phosphoryl transfer reactions catalyzed by tyrosine recombinases: flp h305. Chem Biol 14 (2), 121-9 (2007). [Pubmed | DOI]
  • Chen Y, Bonnet R, Shoichet BK. The Acylation Mechanism of CTX-M beta-Lactamase at 0.88 A Resolution. J Am Chem Soc 129 (17), 5378-5380 (2007). [Pubmed | DOI | Download PDF]
  • Chen Y, Minasov G, Roth TA, Prati F, Shoichet BK. The deacylation mechanism of AmpC beta-lactamase at ultrahigh resolution. J Am Chem Soc 128 (9), 2970-6 (2006). [Pubmed | DOI | Download PDF]
  • Chen Y, Delmas J, Sirot J, Shoichet B, Bonnet R. Atomic Resolution Structures of CTX-M beta-Lactamases: Extended Spectrum Acti vities from Increased Mobility and Decreased Stability. J Mol Biol 348 (2), 349-62 (2005). [Pubmed | DOI | PDB 1YLT | PDB 1YLJ | PDB 1YLP | PDB 1YLW | Download PDF]
  • Chen Y, Shoichet B, Bonnet R. Structure, function, and inhibition along the reaction coordinate of CTX-M beta-lactamases. J Am Chem Soc 127 (15), 5423-34 (2005). [Pubmed | DOI | Download PDF]
  • Conway AB, Chen Y, Rice PA. Structural plasticity of the Flp-Holliday junction complex. J Mol Biol 326 (2), 425-34 (2003). [Pubmed]
  • Chen Y, Rice PA. The role of the conserved Trp330 in Flp-mediated recombination. Functional and structural analysis. J Biol Chem 278 (27), 24800-7 (2003). [Pubmed | DOI]
  • Chen Y, Rice PA. New insight into site-specific recombination from Flp recombinase-DNA structures. Annu Rev Biophys Biomol Struct 32:135-59. (SO - Annu), 135-59 (2003). [Pubmed | DOI]
  • Chen Y, Narendra U, Iype LE, Cox MM, Rice PA. Crystal structure of a Flp recombinase-Holliday junction complex: assembly of an active oligomer by helix swapping. Mol Cell 6 (4), 885-97 (2000). [Pubmed]

Kristin E. Coan
CCB Graduate student

Mechanistic studies of promiscuous inhibition by small molecule aggregation.

Kristin

Publications:

  • Coan KE, Maltby DA, Burlingame AL, Shoichet BK. Promiscuous Aggregate-Based Inhibitors Promote Enzyme Unfolding.. J Med Chem 52 (7), 2067-2075 (2009). [Pubmed | DOI | Faculty of 1000]
  • Coan KE, Shoichet BK. Stoichiometry and physical chemistry of promiscuous aggregate-based inhibitors. J Am Chem Soc 130 (29), 9606-12 (2008). [Pubmed | DOI | Download PDF]
  • Coan KE, Shoichet BK. Stability and equilibria of promiscuous aggregates in high protein milieus. Mol Biosyst 3 (3), 208-13 (2007). [Pubmed | DOI | Download PDF]

Rafaela Salgado Ferreira
CCB Graduate Student (joint with James McKerrow Lab)

Docking to cysteine proteases

Publications:

  • Teotico DG, Babaoglu K, Rocklin GJ, Ferreira RS, Giannetti AM, Shoichet BK. Docking for fragment inhibitors of AmpC beta-lactamase. PNAS 106 (18), 7455-60 (2009). [Pubmed | DOI | Download PDF]

Jérôme Hert, Ph. D.
Postdoc

Using chemoinformatics tools to link chemistry and biology. For more information, please see my webpage.

Publications:

  • Hert J, Keiser MJ, Irwin JJ, Oprea TI, Shoichet BK. Quantifying the Relationships among Drug Classes. J Chem Inf Model 48 (4), 755-765 (2008). [Pubmed | DOI | Download PDF]

John J. Irwin, Ph. D.
Adjunct Assistant Professor

My goal is to make virtual screening more useful for specialists and more accessible for everyone. Our first released product to address these goals is the ZINC database of commerically available compounds for virtual screening. For more information, please see my webpage.

John

Publications:

  • Kolb P, Rosenbaum DM, Irwin JJ, Fung JJ, Kobilka BK, Shoichet BK. Structure-based discovery of beta2-adrenergic receptor ligands. PNAS 106 (16), 6843-6848 (2009). [Pubmed | DOI | Download PDF]
  • Hert J, Keiser MJ, Irwin JJ, Oprea TI, Shoichet BK. Quantifying the Relationships among Drug Classes. J Chem Inf Model 48 (4), 755-765 (2008). [Pubmed | DOI | Download PDF]
  • Babaoglu K, Simeonov A, Irwin JJ, Nelson ME, Feng B, Thomas CJ, Cancian L, Costi MP, Maltby DA, Jadhav A, Inglese J, Austin CP, Shoichet BK. Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase. J Med Chem 51 (8), 2502-11 (2008). [Pubmed | DOI | Download PDF]
  • Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotech 25 (2), 197-206 (2007). [Pubmed | DOI | Download PDF]
  • Huang N, Kalyanaraman C, Irwin JJ, Jacobson MP. Physics-based scoring of protein-ligand complexes: enrichment of known inhibitors in large-scale virtual screening. J Chem Inf Model 46 (1), 243-53 (2006). [Pubmed | DOI]
  • Huang N, Shoichet BK, Irwin JJ. Benchmarking sets for molecular docking. J Med Chem 49 (23), 6789-801 (2006). [Pubmed | DOI | Download PDF]
  • Hermann JC, Ghanem E, Li Y, Raushel FM, Irwin JJ, Shoichet BK. Predicting Substrates by Docking High-Energy Intermediates to Enzyme Structures. J Am Chem Soc 128 (49), 15882-891 (2006). [Pubmed | DOI | Download PDF]
  • Irwin JJ, Shoichet BK. ZINC - A Free Database of Commercially Available Compounds for Virtual Screening. J Chem Inf Model 45 (1), 177-82 (2005). [Pubmed | DOI | Supporting Info | Download PDF]
  • Brenk R, Irwin JJ, Shoichet BK. Here be dragons: docking and screening in an uncharted region of chemical space. J Biomol Screen 10 (7), 667-74 (2005). [Pubmed | DOI | Download PDF]
  • Irwin JJ, Raushel FM, Shoichet BK. Virtual screening against metalloenzymes for inhibitors and substrates. Biochemistry 44 (37), 12316-28 (2005). [Pubmed | DOI | Download PDF]
  • Atreya CE, Johnson EF, Irwin JJ, Dow A, Massimine KM, Coppens I, Stempliuk V, Beverley S, Joiner KA, Shoichet BK, Anderson KS. A molecular docking strategy identifies eosin B as a non-active Site Inhibitor of protozoal bifunctional thymidylate synthase-dihydrofolate reductase. J Biol Chem 278 (16), 14092-100 (2003). [Pubmed | DOI | Faculty of 1000 | Download PDF]
  • Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking (Review). Current Opinion in Chemical Biology 6, 439-46 (2002). [Pubmed | DOI | Download PDF]

Michael Keiser
BMI Graduate Student

I'm developing chemoinformatics techniques to relate proteins based on the statistical similarity of their ligands. I apply this method to questions of polypharmacology, functional relatedness, and virtual screening.

Michael

Publications:

  • Hert J, Keiser MJ, Irwin JJ, Oprea TI, Shoichet BK. Quantifying the Relationships among Drug Classes. J Chem Inf Model 48 (4), 755-765 (2008). [Pubmed | DOI | Download PDF]
  • Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK. Relating protein pharmacology by ligand chemistry. Nat Biotech 25 (2), 197-206 (2007). [Pubmed | DOI | Download PDF]

Peter Kolb, Ph. D.
Postdoc

Discovering enzyme functions through the identification of substrates using DOCK. For more information, please see my webpage.

Publications:

  • Xiang D, Kolb P, Fedorov A, Meier M, Fedorov E, Nguyen T, Sterner R, Almo S, Shoichet B, Raushel F. Functional Annotation and Three-Dimensional Structure of Dr0930 from Deinococcus radiodurans, a Close Relative of Phosphotriesterase in the Amidohydrolase Superfamily. Biochemistry 48 (10), 2237-2247 (2009). [Pubmed | DOI]
  • Kolb P, Rosenbaum DM, Irwin JJ, Fung JJ, Kobilka BK, Shoichet BK. Structure-based discovery of beta2-adrenergic receptor ligands. PNAS 106 (16), 6843-6848 (2009). [Pubmed | DOI | Download PDF]

Matthew Merski, Ph. D.
Postdoc

I am studying the ligand binding capabilities of the cavities in the model proteins T4 phage enzymes and yeast cytochrome C peroxidase. By mutating residues within these cavities and determining the binding affinities of ligands I hope to tease out the energetic terms associated with complex formation.

Michael Mysinger
PSPG Graduate Student

Docking development

Denise Teotico, Ph. D.
Postdoc

I am interested in "fragment-like" drug design and how small molecule docking can be applied to this approach, hopefully leading to the discovery of novel inhibitors of drug-resistant or extended spectrum beta-lactamases.

Publications:

  • Teotico DG, Babaoglu K, Rocklin GJ, Ferreira RS, Giannetti AM, Shoichet BK. Docking for fragment inhibitors of AmpC beta-lactamase. PNAS 106 (18), 7455-60 (2009). [Pubmed | DOI | Download PDF]

Veena L. Thomas
PSPG Graduate student

Activity and Stability Consequences of Evolution of Inhibitor-Resistant Beta-Lactamase Mutants.

Publications:

  • Thomas VL, Golemi-Kotra D, Kim C, Vakulenko SB, Mobashery S, Shoichet BK. Structural consequences of the inhibitor-resistant Ser130Gly substitution in TEM beta-lactamase. Biochemistry 44 ( 26), 9330-9338 (2005). [Pubmed | DOI | Download PDF]