The Shoichet lab seeks to bring chemical reagents to biology,
combining computation and experiment. In a protein-centric
docking, we discover new ligands that complement protein
approach, we discover new targets for known drugs and
reagents. A focus for both is the discovery of reagents to
modulate G-Protein Coupled Receptors (GPCRs).
Developing and testing docking methods in model systems. Two recent papers:
M Fischer et al. Incorporation of protein flexibility & conformational energy penalties in docking screens to improve ligand discovery. Nature Chemistry 6, 575-83 (2014). PMC4539595.
N London, et al. Covalent Docking of Large Libraries for the Discovery of Chemical Probes. Nature Chem. Biol. 10, 1066-72 (2014). PMC4232467.
Colloidal aggregation—the dominant artifact in early drug discovery. Two recent papers:
Owen SC, et al. Colloidal aggregation affects the efficacy of anticancer drugs in cell culture. ACS Chem Biol. 7, 1429-35 (2012). PMC3423826.
McLaughlin CK, et al. Stable Colloidal Drug Aggregates Catch and Release Active Enzymes. ACS Chem Biol. 2016 Jan 15. PMID: 26741163.
Developing & testing systems pharmacology methods. Two recent papers:
E Lounkine et al. Large Scale Prediction and Testing of Drug Activity on Side-Effect Targets. Nature 486, 361-7. (2012). PMC3383642.
H Lin et al. A Pharmacological Organization of G Protein-coupled Receptors. Nature Methods 10, 140-6 (2013). PMC3560304.
Ligand discovery against GPCRs. Two recent papers:
MM Mysinger et al. Structure-based ligand discovery for chemokine receptor CXCR4. Proc Natl Acad Sci. 109, 5517-22 (2012). PMC3325704.
XP Haung et al. Allosteric ligands for the pharmacologically dark receptors GPR68 & GPR65. Nature 527, 477-83 (2015). PMCID in progress.
We are grateful to the NIGMS, the NIH office of the Director, and the US FDA for financial support. We thank and OpenEye Scientific Software for software.