Brian Shoichet Professor

B.Sc., Massachusetts Institute of Technology, 1985
Ph.D., University of California, San Francisco, 1991

PDF, Institute of Molecular Biology, Eugene OR, 1995

Donnelly Centre, 160 College St., Room 604

Computational and Chemical Biology

Go to Lab Homepage

Research Synopsis

A longstanding motivation of the lab is to bring chemical reagents to biological problems. We have traditionally done so by exploiting protein structure to predict new reagents and therapeutic leads. We both develop new computational docking methods and apply these to specific targets, often G-Protein Coupled Receptors (GPCRs).

Allied with this effort is an experimental research program that tests the new computational methods in well-controlled systems, determining x-ray crystal structures and measuring binding thermodynamics. The experimental program has led to unexpected discoveries, including the observation that many drugs and reagents can form colloidal aggregates in solution. This has led us into applications to drug behavior, delivery and formulation.

In counterpoint to the structural view of drug action, we have recently returned to the ideas of classical, chemistry-driven pharmacology, developing methods to relate receptors by the similarity of their ligands, irrespective of their sequence or structure. This changes the map of pharmcological relationships dramatically. Because the new relationships among targets are articulated by small molecules, they may be directly tested, both on isolated receptors and, increasingly, against whole model organisms, such as zebra fish and c. elegans. This, too, returns to classical pharmacology but with the modern molecular tool set. We seek to illuminate the integrated chemical circuits through which drugs and reagents affect whole organisms.  

Selected Publications

MJ Keiser, V Setola, JJ Irwin et al., BK Shoichet* & BL Roth*. Predicting new molecular targets for known drugs. Nature , 462 , 175-81 (2009).

J Carlsson, et al., BL Roth*, BK Shoichet*. Comparing structure-based ligand discovery from a homology model and the crystal structure of the dopamine D 3 receptor . Nature Chem. Biol. 7, 769-78 (2011).

C Laggner, et al., BL Roth,* RT Peterson* & BK Shoichet*. Chemical Informatics and target identification in a Zebrafish phenotypic screen. Nature Chem. Biol., 8, 144-146 (2012).

MM Mysinger, DR Weiss, JJ Ziarek, S Gravel, AK Doak, J Karpiak, N Heveker, BK Shoichet*, BF Volkman* Structure-based Ligand Discovery for Chemokine Receptor CXCR4. Proc Natl Acad Sci. 109, 5517-22 (2012).

Owen SC, Doak AK, Wassam P, Shoichet MS, Shoichet BK. Colloidal aggregation affects the efficacy of anticancer drugs in cell culture . ACS Chem Biol . 7, 1429-35 (2012).

E. Gregori-Puigjané, V. Setola, J Hert, BC Crews, JJ Irwin, Eugen Lounkine | , Larry Marnett, BL Roth* & BK Shoichet* Identifying Mechanism-of-Action Targets for Drugs and Probes. Proc Natl Acad Sci . 109 , 11178-83. (2012).

E Lounkine, et al., BK Shoichet* & L Urban* Large Scale Prediction and Testing of Drug Activity on Side-Effect Targets. Nature 486, 361-7. (2012).

Merski M & Shoichet BK. Engineering a model protein cavity to catalyze the Kemp elimination. Proc Natl Acad Sci 109 , 16179-83 (2012).

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

Fan H, Hitchcock DS, Seidel RD, 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 , 795-803 (2013).

H Lin, MF Sassano, BL Roth* and BK Shoichet*. A Pharmacological Organization of G Protein-coupled Receptors. Nature Methods 10 , 140-6 (2013).


HOME | Faculty | Cette Semaine | News & Events | Research | Resources | Graduate Studies | Undergraduates | Contact | Site Map

Biochemistry Department, University of Toronto homepage

Department of Biochemistry
University of Toronto
Toronto, Canada

© All contents copyright 2011. All rights reserved.

Developed by RNA Studio