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:
A Manglik, H Lin et al., Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185-190 (2016). (link).
XP Haung et al. Allosteric ligands for the pharmacologically dark receptors GPR68 & GPR65. Nature 527, 477-83 (2015). PMCID in progress.
Computational tools as community resources. To support our research we have had to develop and optimize chemical library, docking, and chemoinformatics tools. These we have made freely available to the community:
- The ZINC database of commercially available, dockable molecules.
- The DUD-E benchmark of 102 targets, 30,000 ligands & 1.5 Million decoys.
- DOCK Blaster, a web-based community tool for docking.
- An Excipients Database of FDA-approved drug excipients, their properties, sources, and activities.
- SEA, a chemoinformatics method for predicting targets for ligands.
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.