Overview

The Shoichet lab seeks to bring chemical reagents to biology, combining computation and experiment. In a protein-centric approach, molecular docking, we discover new ligands that complement protein structures. Using a ligand-centric 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).

Projects include:

Developing and testing docking methods in model systems.

Two recent papers:

• Balius TE, Fischer M, Stein RM, Adler TB, Nguyen CN, Cruz A, Gilson MK, Kurtzman T, & Shoichet BK. Testing inhomogeneous solvation theory in structure-based ligand discovery. PNAS 114, E6839-E684 (2017). PMC5565424.
• 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:

• D Duan, H Torosyan, D Elnatan, CK McLaughlin, J Logie, MS Shoichet, DA Agard* & BK Shoichet*. Internal structure and preferential protein binding of colloidal aggregates. ACS Chem Biol. 12, 282–290 (2017). PMC5491102 .
• 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). PMC5161585.
• Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK* & Roth BL.* D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358, 381-386 (2017). PMC5856174.

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.