# Is there a common allosteric binding site for all GPCRs?

> **NIH NIH R15** · UNIVERSITY OF THE SCIENCES PHILADELPHIA · 2020 · $203,137

## Abstract

Project Summary
 G-protein coupled receptors (GPCRs) represent the largest superfamily of human
proteome with more than 800 members. Given the key role of GPCRs in signal
transduction across membranes, GPCRs are the number one drug target, accounting for
approximately 25% of the current drugs in the market. Despite significant progresses in
drug discovery targeting GPCRs, many pharmaceutically important GPCRs remain
elusive. In recent years, a novel venue has been reported to exploit the allosteric sites
on them for the development of drugs to treat various diseases. Identifying the allosteric
sites on GPCRs, however, remains a challenge. This proposal aims to explore the
existence of a common allosteric site below the middle of the transmembrane domain
that spatially overlaps with the G-protein binding site for all human GPCRs. The long-
term objective of this project is to understand the mechanism of allosteric regulations in
GPCRs.
 For this proposal, proposed works will include two specific Aims. Aim I is to identify
allosteric antagonists and agonists of eight representative GPCRs from Class A, B, C
and F that bind to the proposed common allosteric site on these GPCRs through in silico
screening and in vitro test. For this aim, two GPCRs with known structure, one in its
inactive conformation and one in its active conformation, will be chosen from each of the
four non-sensory GPCR Classes, A, B, C and F. Then in silico screening against ZINC
database will be performed using each structure. For top-ranked compounds, their
binding stability and binding affinity in the binding site will be computationally studied
using molecular dynamics simulations. Finally, for those top-ranked antagonists and
agonists, in vitro activity studies and site-specific mutagenesis studies will be carried out.
Aim II is to improve the selectivity and potency of the identified GLP-1R allosteric agonist
through structure-based molecule design and experimental test. This aim will be carried
out by: 1) obtain the active structure of both GLP-1R and GCGR and run molecular
dynamics simulations; 2) compare the conformation snapshots from GLP-1R simulations
with those of GCGR and identify one conformation of GLP-1R that have the largest
structural difference at the proposed allosteric site from all GCGR conformations; 3)
dock the GLP-1R allosteric agonist to the allosteric site in the identified GLP-1R
conformation from las step and perform in virtual combinatorial library design to generate
optimized compounds; 4) re-dock the top-ranked compounds from last step to the same
allosteric site on the GCGR conformation most similar to GLP-1R conformation; and 5)
in vitro assay test the lowest ranked compounds from last step.
 Given the strategic location of this common binding site, the success of this proposal
could provide a useful venue for biological studies and therapeutic discovery targeting
various GPCRs.

## Key facts

- **NIH application ID:** 10114528
- **Project number:** 1R15GM140406-01
- **Recipient organization:** UNIVERSITY OF THE SCIENCES PHILADELPHIA
- **Principal Investigator:** Zhijun Li
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,137
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114528

## Citation

> US National Institutes of Health, RePORTER application 10114528, Is there a common allosteric binding site for all GPCRs? (1R15GM140406-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10114528. Licensed CC0.

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