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Is there a common allosteric binding site for all GPCRs?

Award Number: R15GM140406
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Is there a common allosteric binding site for all GPCRs? - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2020	SAINT JOSEPHS UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	4/2/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	SAINT JOSEPHS UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	003	2	8/14/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	11/13/2022	NEW	$0
2023	2020	SAINT JOSEPHS UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	002	2	8/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2020	ST JOSEPH'S UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	12/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $103,937 )
2022	2022	ST JOSEPH'S UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	002	2	8/26/2022	SUPPLEMENT FOR EXPANSION	$100,000
2022	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	6/30/2022	NEW	-$224,363
2022	2020	ST JOSEPH'S UNIVERSITY	5600 CITY AVE	PHILADELPHIA	PA	19131	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	7/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$228,300
														Subtotal = $103,937

Issue Date FY: 2020 ( Subtotal = $427,500 )
2020	2020	UNIVERSITY OF THE SCIENCES IN PHILADELPHIA	600 S 43RD ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	9/10/2020	NEW	$427,500
														Subtotal = $427,500

Grand Total All Awards = $531,437

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Is there a common allosteric binding site for all GPCRs?

Award Number: R15GM140406

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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