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Drug Discovery on Pentameric Ligand-Gated Ion Channels

Wells, Marta (2018) Drug Discovery on Pentameric Ligand-Gated Ion Channels. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Pentameric ligand-gated ion channels (pLGICs) are extensively involved in fast synaptic transmission and play a key role in many different neurological processes, such as pain sensation, memory, and addiction. These receptors are known targets for a variety of established pharmacological agents with diverse clinical uses, but recent major progress in our understanding of pLGIC structure-function relationships allows for the enhanced discovery of new drugs with improved therapeutic potential and reduced adverse effects. This dissertation presents the integrated computational and experimental techniques employed towards this end for two different pLGICs, the α3 glycine receptor (GlyR) and the α7 nicotinic acetylcholine receptor (nAChR). Three primary accomplishments resulted from this work. First, an ensemble-based virtual screening protocol was developed to target the GlyR transmembrane domain (TMD). Small-scale screening calculations were performed as a pilot study and validated by functional electrophysiology measurements, resulting in a hit rate of over 90% success. Second, this screening protocol was expanded to identify compounds specifically targeting the cannabinoid- binding site in α3GlyR. The lead compound from in vitro functional validation experiments progressed to in vivo behavioral tests in mice and was found to be a potent analgesic for inflammatory pain. Third, experimental restraints from nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy were applied to determine the first structures of the α7nAChR intracellular domain (ICD). Although many different pLGIC structures have been solved in recent years, no structure obtained so far contains a complete ICD. This domain is an important target for therapeutic interventions for a variety of neurological disorders associated with intracellular signal transduction, but structure-based drug discovery is impossible without accurate structural information. The α7nAChR ICD structures determined here lay the foundation for future screening efforts in a previously unexplored area of drug discovery.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wells, Martammw88@pitt.edummw88
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorTang,
Committee ChairKurnikova,
Committee MemberBahar,
Committee MemberXu,
Date: 30 August 2018
Date Type: Publication
Defense Date: 3 August 2018
Approval Date: 30 August 2018
Submission Date: 13 August 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 144
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: structural biology, Cys-loop receptor
Date Deposited: 30 Aug 2018 21:04
Last Modified: 30 Aug 2023 05:15


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