Computational Investigation of Potential Negative Allosteric Modulator (NAM) Binding Sites for Cannabinoid CB2 Receptor

Rosario, Adrian Jacob (2024) Computational Investigation of Potential Negative Allosteric Modulator (NAM) Binding Sites for Cannabinoid CB2 Receptor. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

The aim of this project is to predict the residues in site C of cannabinoid receptor 2 (CB2) that could play an important role in TM17-1 NAM binding. Prediction of the important binding sites for allosteric modulator (AM) binding is significant as the information from this study could prove to be helpful in the design of future AM drugs. Allosteric modulators have several advantages over drugs targeting the orthosteric or active site, including the ceiling effect, which prevents drug overdoses, biased signaling, and greater specificity to the receptor, which in combination reduces the chance of adverse reactions occurring. We used a combination of molecular docking and structural protein analyses to predict the residues for allosteric modulator binding in site C for TM17-1 NAM binding. Based on the computational studies conducted, we showed that Tyr70, Arg131, Leu 243, and Ser 303 potentially have significant interactions with TM17-1 in site C of the CB2 receptor. Site-directed mutagenesis will be used in future studies to validate our hypothesis. We hypothesize that TM17-1 may act as a CB2 NAM by preventing Tyr70, and Arg131 in CB2 from forming key interactions with Gαi, thus preventing CB2 agonist modulation of this pathway.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Rosario, Adrian Jacob ajr244@pitt.edu ajr244
ETD Committee:	Title Member Email Address Pitt Username ORCID Thesis Advisor McGuire, Terence Francis tfm1@pitt.edu tfm1 Committee Member Xie, Xiang-Qun sean.xie@pitt.edu sean.xie Committee Member Jun, Jaden Jungho jjj46@pitt.edu jjj46 Committee Member Feng, Zhiwei zhf11@pitt.edu zhf11
Date:	29 April 2024
Date Type:	Publication
Defense Date:	28 March 2024
Approval Date:	29 April 2024
Submission Date:	19 April 2024
Access Restriction:	2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages:	65
Institution:	University of Pittsburgh
Schools and Programs:	School of Pharmacy > Pharmaceutical Sciences
Degree:	MS - Master of Science
Thesis Type:	Master's Thesis
Refereed:	Yes
Uncontrolled Keywords:	CB2, molecular docking, allosteric modulators, site C
Date Deposited:	29 Apr 2024 13:44
Last Modified:	29 Apr 2024 13:44
URI:	http://d-scholarship.pitt.edu/id/eprint/46198

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• Computational Investigation of Potential Negative Allosteric Modulator (NAM) Binding Sites for Cannabinoid CB2 Receptor. (deposited UNSPECIFIED)

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