Illuminating The Druggable GPCR-OME

Bryan Roth, M.D., Ph.D.
Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics
Department of Pharmacology
School of Medicine
University of North Carolina, Chapel Hill

Brian Shoichet, Ph.D.
Professor
Department of Pharmaceutical Chemistry
University of California
San Francisco

Contacts

Bryan Roth’s lab: https://pdsp.unc.edu/rothlab/
Brian Shoichet’s lab: https://www.bkslab.org/

Bryan Roth: @zenbrainestM
Roth Lab: @RothlabUNC

Overview

Collaborative work by Dr. Bryan Roth and Dr. Brian Shoichet focuses on illuminating the druggable GPCR-ome by two-pronged approach of empirical screening of drugs followed by computational screening against modeled structures of the GPCR to produced optimized lead compounds. Their work has led to discovery of molecule “ogerin” binding previously orphaned, GPR68. Additional collaborators include:

John Irwin, PhD (UCSF) – http://irwinlab.compbio.ucsf.edu/
Jian Jin, Ph.D. lab (MSSM) - https://labs.icahn.mssm.edu/jinlab/
Pablo Ariel, PhD from UNC Light Sheet Core - https://www.med.unc.edu/microscopy
Dale Cowley, PhD from UNC Mouse Genetics Core - https://www.med.unc.edu/amc/services/å

NIH grant number: 1U24 DK116195-01

Progress on IDG project as tracked by Protein Illumination Timeline:
GPCR Mice: https://druggablegenome.net/ProteinTimelineGPCRmice
GPCR Probes: https://druggablegenome.net/ProteinTimelineGPCRprobes

Expression images on A Mouse Imaging Server (AMIS):
Images of mouse expression of GPCR IDG proteins: http://amis.docking.org

DRGC-GPCR recent publications:

Ultra-large library docking for discovering new chemotypes.
Lyu J, Wang S, Balius TE, Singh I, Levit A, Moroz YS, O'Meara MJ, Che T, Algaa E, Tolmachova K, Tolmachev AA, Shoichet BK, Roth BL, Irwin JJ., Nature. 2019 Feb;566(7743):224-229. doi: 10.1038/s41586-019-0917-9. Epub 2019 Feb 6.,PMID: 30728502
How structure informs and transforms chemogenetics.
Roth BL., Curr Opin Struct Biol. 2019 Feb 25;57:9-16. doi: 10.1016/j.sbi.2019.01.016. Review. PMID: 30818201
Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets.
Weiss DR, Karpiak J, Huang XP, Sassano MF, Lyu J, Roth BL, Shoichet BK., J Med Chem. 2018 Aug 9;61(15):6830-6845. doi: 10.1021/acs.jmedchem.8b00718. Epub 2018 Jul 24., PMID: 29990431
Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone.
Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL., Nature. 2018 Mar 8;555(7695):269-273. doi: 10.1038/nature25758. Epub 2018 Jan 24., PMID: 29466326
Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs.
McCorvy JD, Butler KV, Kelly B, Rechsteiner K, Karpiak J, Betz RM, Kormos BL, Shoichet BK, Dror RO, Jin J, Roth BL. Nat Chem Biol. 2018 Feb;14(2):126-134. doi: 10.1038/nchembio.2527. Epub 2017 Dec 11., PMID: 29227473