GPR55 is a lysophosphatidylinositol (LPI)-sensitive G-protein coupled receptor (GPCR) that recognizes a sub- set of cannabinoid CB1 and CB2 ligands. The goal of the proposed project is to understand the functional features of GPR55 that may define mechanisms of drug-receptor interactions relevant to physiological and pathophysiological function, including drug abuse. GPR55 has been implicated in inflammatory pain, neuropathic pain, metabolic disorder, bone and neurological development, and cancer, indicating the real potential of GPR55 ligands as therapeutics. Each of these areas alone is medically important and each would benefit by the use of selective agonists and antagonists to further studies. While selective agonists and antagonists for GPR55 from a number of diverse scaffolds have been identified, no low nanomolar potency ligands have been confirmed for this receptor, nor is there a radioligand developed to characterize binding. We have recently identified the first set of GPR55 residues important for agonist signaling and for GPR55 activation. This information should aid in the rational design of next generation GPR55 ligands, using our evolving molecular model. The goal of this proposal is to use structure-based design and cheminformatics tools to develop structure-activity relationships for selected scaffolds, leading to the identification of low nanomolar ligands that retain high receptor selectivity.
We aim to discover nanomolar potency GPR55 ligands using a combination of molecular modeling, chemoinformatics, high-throughput screening and site directed mutagenesis. We will dissect the specific signaling pathways governing GPR55 activity as well as investigate ligand bias.

Public Health Relevance

The GPR55 receptor is a promising therapeutic target for disorders including inflammatory pain, neuropathic pain, metabolic disorder, bone development, and cancer. Progress in the development of pharmacotherapies has been prevented due to the lack of specific, low nanomolar, high potency ligands. The goal of this R01 proposal is to use structure-based design and cheminformatic tools to identify low nanomolar, high potency agonists and antagonists for GPR55.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA045698-03
Application #
9891998
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
2018-05-15
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122