In silico investigations of the ionotropic cannabinoid receptor TRPV1
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Chante Muller (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
- Advisor
- Patricia Reggio
Abstract: Whether caused by inflammation or dysfunctional nerves, chronic pain affects nearly 10% of the world’s population. Since there are few treatments that are effective while being noninvasive and non-addictive, new targets are being explored. Found in the peripheral nervous system, the transient receptor potential subfamily vanilloid type 1 (TRPV1) ion channel can be activated by a plethora of exogenous and endogenous stimuli including the spicy compound found in chili peppers, capsaicin, as well as temperatures above 43oC and acidic conditions. TRPV1, having the ability to be modulated by cannabinoid ligands, acts as an ionotropic cannabinoid receptor (ICR). Chapter II reviews cannabinoid ligands that can modulate ionotropic cannabinoid receptors, including TRPV1. The endocannabinoid anandamide has been shown to have a similar binding affinity to TRPV1 as capsaicin and can rapidly desensitize the channel producing an analgesic effect. Models of the open and closed structures of TRPV1 were constructed for use in molecular dynamics simulations. Chapter III details the construction of the models, as well as observed interactions between the endogenous ligand anandamide and TRPV1 in a novel location across 10+ µs of simulation time. TRPV2, a close cousin of TRPV1 and another ICR, was recently resolved with the phytogenic cannabinoid cannabidiol (CBD). From Chapter II, CBD is shown to modulate some, though not all, ICRs. Chapter IV focuses on the cryo-EM structure of TRPV2 resolved with CBD (PDB: 6U88) and analyzes the putative binding site via sequence alignment and structural analyses, comparing these features to the comparable site among the other ICRs, lending credence to this novel CBD binding site in other ICRs. Chapter V focuses on the results of additional long timescale MD simulations of TRPV1 in the presence of anandamide. In two independent runs, anandamide was observed to activate TRPV1 in a novel location between helices S1-S4. The colocalization of canonical cannabinoid receptor CB2 and TRPV1 presents an interesting dynamic, especially when considering the crosstalk of the two receptors presumed to exist. CB2 and TRPV1 are implicated various disorders, making them prime targets for the identification and development of dual modulators. Chapter VI describes a virtual screening protocol used to screen ChEMBL indexed CB2 and TRPV1 agonists at the opposing receptor, leading to the identification of moieties that may be relevant in dual modulatory ligands.
In silico investigations of the ionotropic cannabinoid receptor TRPV1
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Created on 8/1/2022
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Additional Information
- Publication
- Dissertation
- Language: English
- Date: 2022
- Keywords
- Anandamide, Cannabinoids, TRP channels, TRPV1
- Subjects
- Chronic pain $x Treatment
- Cannabinoids $x Receptors
- Ligands (Biochemistry)
- TRP channels