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]

Trent Balius
Postdoc

I am working on performing large-scale docking and improving automated docking procedures. The objective is to preform proteomic-scale docking and analyse the results in cool ways to learn about protein relationships from a ligand-centred perspective. My goal is to obtain a faculty position at a research university were I plan to continue DOCK development and perform research focused on drug discovery and improving therapeutics. For more information about me visit my webpage: http://docking.org/~tbalius/

Trent

Sarah Barelier, Ph. D.
Postdoc

I am interested in fragment-based approaches applied to drug design and substrate discovery:

  • Fragment-based screening against AmpC Beta-Lactamase: how to expand our exploration of chemical space using fragment molecules?
  • Analyzing the potential of fragment molecules as tools for enzyme function prediction: the Amidohydrolase Superfamily as a case study. These two projects involve fragment docking, enzymatic assays and X-ray crystallography.

Publications from PhD



Sarah

Publications:

  • Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, Shoichet BK, Prati F.. Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo.. Proc Natl Acad Sci 109 (43), 17448-53 (2012). [Pubmed | DOI]

Ryan G Coleman, Ph. D.
Postdoc

I am working on the ligand sampling methodology in docking.

http://ryancoleman.name

Ryan

Publications:

  • Cameron RT, Coleman RG, Day JP, Yalla KC, Houslay MD, Adams DR, Shoichet BK, Baillie GS.. Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).. Biochem. Pharmacol. 85 (9), 1297-1305 (2013). [Pubmed | DOI]
  • Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nature Chemical Biology 7 (11), 769-778 (2011). [Pubmed | DOI | NRDD Highlight | F1000 Evaluation | Download PDF]

Allison Doak

I have taken over the World of Small Molecule Aggregation from the amazing Dr. Kristin Coan. Main focus: can/do small molecules form colloidal particles in biologically relevant environments?

(Un-related) Publication:

Galli LM, Knight SR, Barnes TL, Doak AK, Kadzik RS, Burrus LW. Identification and characterization of subpopulations of Pax3 and Pax7 expressing cells in devloping chick somites and limb buds. Dev Dyn 237 (7), 1862-74 (2008).

Allison

Publications:

  • Sassano MF, Doak AK, Roth BL, Shoichet BK.. Colloidal aggregation causes inhibition of g protein-coupled receptors.. J Med Chem. 56 (6), 2406-2414 (2013). [Pubmed | DOI | Faculty of 1000]
  • Mysinger MM, Weiss DR, Ziarek JJ, Gravel S, Doak AK, Karpiak J, Heveker N, Shoichet BK, Volkman BF. Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4. Proc Natl Acad Sci 109 (14), 5517-22 (2012). [Pubmed | DOI]
  • Doak AK, Wille H, Prusiner SB, Shoichet BK. Colloid Formation by Drugs in Simulated Intestinal Fluid. J. Med. Chem. 53 (10), 4259-4265 (2010). [Pubmed | DOI | Download PDF]

Oliv Eidam, Ph. D.
Postdoc

I use docking, modeling and crystallography to find new cancer therapeutics and to fight bacterial resistance against penicillin-like antibiotics. My work is in collaborations with the NIH Chemical Genomics Center (NCGC), the Structural Genomics Consortium (SGC) in Oxford and dedicated synthetic chemists from the University of Modena in Italy.
I am also interested into fragment-based drug discovery.

Publications from PhD

Oliv

Publications:

  • Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, Shoichet BK, Prati F.. Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo.. Proc Natl Acad Sci 109 (43), 17448-53 (2012). [Pubmed | DOI]
  • Bonazzi S, Eidam O, Guttinger S, Wach JY, Zemp I, Kutay U, Gademann K. Anguinomycins and derivatives: total syntheses, modeling, and biological evaluation of the inhibition of nucleocytoplasmic transport.. Journal of the American Chemical Society 132 (4), 1432-42 (2010). [Pubmed | DOI | Models | ACS Chemical Biology Spotlight]
  • Ferreira RS, Simeonov A, Jadhav A, Eidam O, Mott BT, Keiser MJ, McKerrow JH, Maloney DJ, Irwin JJ, Shoichet BK. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.. Journal of Medicinal Chemistry 53 (13), 4891-905 (2010). [Pubmed | DOI | Download PDF]
  • Eidam O, Romagnoli C, Caselli E, Babaoglu K, Pohlhaus DT, Karpiak J, Bonnet R, Shoichet BK, Prati F. Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as Beta-Lactamase Inhibitors.. Journal of Medicinal Chemistry , (2010). [Pubmed | DOI | Download PDF]

Hao Fan, Ph. D.
Postdoc

Develop an integrated method combining protein modeling and ligand docking, for protein-ligand complex structure prediction and ligand discovery. Predict structures and functions for amidohydrolases.

Hao

Publications:

  • Fan H, Hitchcock DS, Seidel RD 2nd, Hillerich B, Lin H, Almo SC, Sali A, Shoichet BK, Raushel FM.. Assignment of pterin deaminase activity to an enzyme of unknown function guided by homology modeling and docking. J Am Chem Soc 135 (2), 795-803 (2013). [Pubmed | DOI]
  • Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nature Chemical Biology 7 (11), 769-778 (2011). [Pubmed | DOI | NRDD Highlight | F1000 Evaluation | Download PDF]
  • Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, Giacomini KM, Sali A. Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. PNAS 108 (38), (2011). [Pubmed | DOI | Download PDF]
  • Kamat SS, Fan H, Sauder JM, Burley SK, Shoichet BK, Sali A, Raushel FM. Enzymatic deamination of the epigenetic base N-6-methyladenine. J Am Chem Soc 133 (7), 2080-3 (2011). [Pubmed | DOI | Download PDF]
  • Fan H, Schneidman-Duhovny D, Irwin JJ, Dong G, Shoichet BK, Sali A. Statistical Potential for Modeling and Ranking of Protein-Ligand Interactions. Journal of Chemical Information and Modeling 51 (12), 3078-3092 (2011). [Pubmed | DOI]

Marcus Fischer, Ph. D.
Postdoc

I'm working with model systems to develop and experimentally test computational methods for ligand discovery. For those simplified, engineered cavities the cycle between prediction and testing is rapid and informative. It is one of the few systems where failure is illuminating, even sought. I have a general interest in understanding phenomena underlying protein-ligand interactions which I study using a variety of complementary methods.
Other Publications



Marcus

Inbar Fish

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:

  • Laggner C, Kokel D, Setola V, Tolia A, Lin H, Irwin JJ, Keiser MJ, Cheung CYJ, Minor DL, Roth BL, Peterson RT, Shoichet BK. chemical informatics and target identification in a zebrafish phenotypic screen. Nature Chemical Biology 8 (2), 144-146 (2012). [Pubmed | DOI]
  • Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK. Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nature Chemical Biology 7 (11), 769-778 (2011). [Pubmed | DOI | NRDD Highlight | F1000 Evaluation | Download PDF]
  • Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, Giacomini KM, Sali A. Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. PNAS 108 (38), (2011). [Pubmed | DOI | Download PDF]
  • Fan H, Schneidman-Duhovny D, Irwin JJ, Dong G, Shoichet BK, Sali A. Statistical Potential for Modeling and Ranking of Protein-Ligand Interactions. Journal of Chemical Information and Modeling 51 (12), 3078-3092 (2011). [Pubmed | DOI]
  • Ferreira RS, Simeonov A, Jadhav A, Eidam O, Mott BT, Keiser MJ, McKerrow JH, Maloney DJ, Irwin JJ, Shoichet BK. Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.. Journal of Medicinal Chemistry 53 (13), 4891-905 (2010). [Pubmed | DOI | Download PDF]
  • Carlsson J, Yoo L, Gao ZG, Irwin JJ, Shoichet BK, Jacobson KA. Structure-based discovery of A2A adenosine receptor ligands.. Journal of Medicinal Chemistry 53 (9), 3748-55 (2010). [Pubmed | DOI | Download PDF]
  • Keiser MJ, Irwin JJ, Shoichet BK. The chemical basis of pharmacology. Biochemistry 49 (48), 10267-76 (2010). [Pubmed | DOI | Download PDF]
  • Yadav PN, Abbas AI, Farrell MS, Setola V, Sciaky N, Huang XP, Kroeze WK, Crawford LK, Piel DA, Keiser MJ, Irwin JJ, Shoichet BK, Deneris ES, Gingrich J, Beck SG, Roth BL. The presynaptic component of the serotonergic system is required for clozapine's efficacy. Neuropsychopharmacology 36 (3), 638-51 (2010). [Pubmed | DOI | Download PDF]
  • 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]
  • Irwin JJ, Shoichet BK, Mysinger MM, Huang N, Colizzi F, Wassam P, Cao Y. Automated docking screens: a feasibility study.. Journal of Medicinal Chemistry 52 (18), 5712-20 (2009). [Pubmed | DOI | Download PDF]
  • Kolb P, Ferreira RS, Irwin JJ, Shoichet BK. Docking and chemoinformatic screens for new ligands and targets.. Current opinion in biotechnology 20 (4), 429-36 (2009). [Pubmed | DOI | Download PDF]
  • Kolb P, Irwin JJ. Docking screens: right for the right reasons?. Current Topics in Medicinal Chemistry 9 (9), 755-70 (2009). [Pubmed]
  • 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]

Joel Karpiak
Graduate Student

Research summary: Computational methods for the discovery of novel G protein-coupled receptor drugs and experimentally determining and verifying their mechanism of action.

Publications:

  • Mysinger MM, Weiss DR, Ziarek JJ, Gravel S, Doak AK, Karpiak J, Heveker N, Shoichet BK, Volkman BF. Structure-based ligand discovery for the protein-protein interface of chemokine receptor CXCR4. Proc Natl Acad Sci 109 (14), 5517-22 (2012). [Pubmed | DOI]
  • Eidam O, Romagnoli C, Caselli E, Babaoglu K, Pohlhaus DT, Karpiak J, Bonnet R, Shoichet BK, Prati F. Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as Beta-Lactamase Inhibitors.. Journal of Medicinal Chemistry , (2010). [Pubmed | DOI | Download PDF]

Magdalena Korczynska
Postdoc

I received my Doctoral dissertation from McGill University, in the field of X-ray crystallographic studies of antibiotic resistance enzymes. Now, as a Postdoctoral Fellow, I am involved with the Enzyme Function Initiative (EFI) project (http://enzymefunction.org/). This is a multi institutional, collaborative endeavor that has been set up to identify an efficient work flow to reliably identify in vitro enzymatic activity and in vivo metabolic function from sequence. My specific contribution to the EFI project is to computationally predict the function of enzymes based on the complementary of metabolic substrates to the three dimensional protein structure.

Magdalena

Publications:

  • Ornelas A, Korczynska M, Ragumani S, Kumaran D, Narindoshvili T, Shoichet BK, Swaminathan S, Raushel FM. Functional annotation and three-dimensional structure of an incorrectly annotated dihydroorotase from cog3964 in the amidohydrolase superfamily. Biochemistry 52 (1), 228-238 (2013). [Pubmed | DOI]

Henry Lin
Graduate Student

Henry

Publications:

  • Fan H, Hitchcock DS, Seidel RD 2nd, Hillerich B, Lin H, Almo SC, Sali A, Shoichet BK, Raushel FM.. Assignment of pterin deaminase activity to an enzyme of unknown function guided by homology modeling and docking. J Am Chem Soc 135 (2), 795-803 (2013). [Pubmed | DOI]
  • Lin H, Sassano MF, Roth BL, Shoichet BK.. A pharmacological organization of G protein-coupled receptors.. Nat. Methods 10 (2), 140-146 (2013). [Pubmed | DOI | Faculty of 1000]
  • Laggner C, Kokel D, Setola V, Tolia A, Lin H, Irwin JJ, Keiser MJ, Cheung CYJ, Minor DL, Roth BL, Peterson RT, Shoichet BK. chemical informatics and target identification in a zebrafish phenotypic screen. Nature Chemical Biology 8 (2), 144-146 (2012). [Pubmed | DOI]
  • Avasthi P, Marley A, Lin H, Gregori-Puigjane E, Shoichet BK, von Zastrow M, Marshall WF. A Chemical Screen Identifies Class A G-Protein Coupled Receptors As Regulators of Cilia. ACS Chem Biol (epub), (2012). [Pubmed | DOI]

Nir London
Postdoc

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.

Publications:

  • Merski M, Shoichet BK.. The Impact of Introducing a Histidine into an Apolar Cavity Site on Docking and Ligand Recognition.. J. Med. Chem. , (2013). [Pubmed | DOI]
  • Merski M,Shoichet BK. Engineering a model protein cavity to catalyze the Kemp elimination. Proceedings of the National Academy of Sciences of the United States of America 109 (40), 16179-1618 (2012). [Pubmed | DOI]

Elisabet Gregori Puigjane, Ph. D.
Postdoc

My focus is on chemoinformatics methods. I am currently working in developing the Similarity Ensemble Approach methodology and applying it to the discovery of novel targets for drugs and other small molecules.

Elisabet

Gabriel Rocklin
Biophysics Graduate Student (Joint with Ken Dill's lab)

I am working on applying molecular dynamics simulations and alchemical free energy methods to the problem of predicting absolute binding free energies in the model binding sites. I hope to increase the speed and reliability of these calculations, and also to use this highest level of computational theory available to learn lessons about ligand binding that will applicable to docking.

Gabriel

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]
  • Boyce SE, Mobley DL, Rocklin GJ, Graves AP, Dill KA, Shoichet BK. Predicting Ligand Binding Affinity with Alchemical Free Energy Methods in a Polar Model Binding Site.. Journal of Molecular Biology , (2009). [Pubmed | DOI | Download PDF]

Teague Sterling
System Administrator

I work on the ZINC Database and other web projects.

Teague

Dahlia Weiss, Ph. D.
Postdoc

I am interested in applying virtual screening to find better drug leads for G-protein Coupled Receptor (GPCR) targets. My research focuses on appying homology modeling and virtual screening to "difficult" targets, such as protein- and peptide- binding GPCRs. In addition, I am interested in the rational design of poly-pharmacology, namely the design of molecules with predefined specificity and efficacy for a panel of GPCRs. This includes multiple targets (to which binding in beneficial) and anti-targets (to which binding is detrimental). For publications visit: http://www.rationaldrugdesign.org/research.html

Dahlia

Publications:

  • Weiss DR, Ahn S, Sassano MF, Kleist A, Zhu X, Strachan R, Roth BL, Lefkowitz RJ, Shoichet BK.. Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor.. ACS Chem. Biol. , (2013). [Pubmed | DOI]

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