SC15: Introduction to Allosteric Modulators and Biased Ligands of GPCRs
Wednesday, September 21 | 7:00 - 9:30 pm


Instructors:
Annette Gilchrist, Ph.D., Professor, Pharmacology, Midwestern University
Corey Hopkins, Ph.D., Associate Professor, Department of Pharmaceutical Sciences, University of Nebraska Medical Center

Allosteric modulators and pathway-biased ligands represent novel therapeutic approaches for achieving more selective actions with regards to G protein-coupled receptors (GPCRs). However the identification and characterization of such compounds can be challenging due in part to ‘context-dependent phenomena’. Aimed at scientists working on GPCRs this course will provide information on the identification and validation of allosteric, pathway-biased drugs including emerging screening approaches, practical tips and tools for identification and validation, and the structural basis underlying such drugs.

Introduction to Allosterism and Biased Signaling (Annette Gilchrist)

  • Definitions, conceptual and practical explanations of allosteric modulators and pathway biased ligands and their relationships to one another
  • Receptor structure with an emphasis on known allosteric binding sites
  • Current status of the field (allosteric and biased ligands in development or on the market)

Screening and Validating Allosteric and Biased Ligands (Corey Hopkins)

  • Screening, quantification and validation of allosteric and biased ligands
  • Differentiating allosteric v. bitopic v. orthosteric ligands
  • Complexities and challenges for discovery:
    • the problem with potency
    • molecular switches
    • probe dependence
    • observational versus ligand bias

Practical Advice and Discussions (Annette Gilchrist and Corey Hopkins):

  • Q&A from audience
  • Come with your examples/real-lab problems

Instructors:


Annette_GilchristAnnette Gilchrist, Ph.D., Professor, Pharmacology, Midwestern University

Dr. Gilchrist works on allosteric and/or biased modulators for a number of different GPCRs including PAR1, CCR1, and FFAR2. She also serves as the Senior Online Editor for British Journal of Pharmacology and British Journal of Clinical Pharmacology. In addition to editing the book “GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions” published by John Wiley and Sons she has written chapters on G protein signaling and CCR1 antagonists.

Currently she is working with Dr. Paula Stern as a guest editor for Frontiers in Endocrinology for a themed issue on “Chemokines and Bone”. Previously, she was with Cue Biotech and Caden Biosciences, companies she co-founded that focused on GPCRs and used a novel approach to identify allosteric compounds based on their ability to modulate GPCR/G protein coupling (US Patent Numbers 7,208,279 and 7,294,472). Prior to that Dr. Gilchrist worked as an Assistant Research Professor in the Department of Molecular Pharmacology & Biological Chemistry at Northwestern University where she developed a set of unique tools known as minigene vectors (US Patent Number 6,559,128). Minigene vectors allow one to dissect out the G protein that mediates a given physiological function and they have been widely adopted by researchers around the world. Preceding that Dr. Gilchrist was a postdoctoral fellow with Dr. Heidi Hamm. In this setting, she identified high affinity peptides that mimic the C-terminus of Ga, and were later used for crystallization of rhodopsin. Dr. Gilchrist’s work on GPCRs began with her graduate studies in which she studied signaling of chemokine receptors through tyrosine kinases and phosphatases. Dr. Gilchrist has a PhD in Immunology from the University of Connecticut Health Center and a MS in Biochemistry from the University of Connecticut.

Corey_HopkinsCorey Hopkins, Ph.D., Associate Professor, Department of Pharmaceutical Sciences, University of Nebraska Medical Center

In 2008, Professor Corey Hopkins joined the faculty in the Department of Pharmacology at the Vanderbilt University Medical Center, Nashville, TN, USA, where he is also the Associate Director of Medicinal Chemistry for Vanderbilt’s Center for Neuroscience Drug Discovery. Dr. Hopkins lead’s a team of chemists focusing on mGlu4 allosteric modulation for the treatment of Parkinson’s disease. Prior to joining Vanderbilt, Dr. Hopkins was a member of the medicinal chemistry department of Sanofi-Aventis Pharmaceuticals (2001 – 2005; 2006 – 2008) and P&G Pharmaceuticals where he worked on a number of CNS-related therapeutic targets (multiple sclerosis, depression) and inflammation-related targets (asthma, rheumatoid arthritis). He received his Ph.D. in Organic Chemistry in 2002 from the University of Pittsburgh, USA, under the direction of Professor Peter Wipf. Dr. Hopkins is the author of over 75 peer-reviewed manuscripts, review articles and book chapters. In addition, he is the co-inventor on over 20 patents.