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Computational Predicting CB2 Allosteric Binding Sites to Promote the Allosteric Modulators Design

Yuan, Jiayi (2022) Computational Predicting CB2 Allosteric Binding Sites to Promote the Allosteric Modulators Design. Master's Thesis, University of Pittsburgh. (Unpublished)

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Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of the CB2-orthosteric ligand-allosteric modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G, and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-β-caryophyllene (TBC), and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Yuan, JiayiJIY106@pitt.eduJIY106
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKirisci, Leventlevent@pitt.edulevent
Committee MemberXie, Xiang-Qun (Sean)sean.xie@pitt.edusean.xie
Committee MemberWang,
Committee MemberFeng, Zhiweizhf11@pitt.eduzhf11
Date: 6 April 2022
Date Type: Publication
Defense Date: 24 March 2022
Approval Date: 6 April 2022
Submission Date: 5 April 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 59
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: cannabinoid receptor 2; allosteric binding site; positive allosteric modulators; negative allosteric modulators
Related URLs:
Date Deposited: 06 Apr 2022 17:33
Last Modified: 06 Apr 2022 17:33


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