SK Channel Modulators as Drug Candidates and Pharmacological Tools

<p>The small- and intermediate-conductance Ca2+ activated K + (SK/IK) channels play a fundamental role in the regulation of neurons in the central nervous system. In animal models, SK/IK channel positive modulators have been shown to be effective in reducing the symptoms of neurological diseases such as ataxia. Ataxia is a lethal neurological rare disease characterized by lack of balance and incoordination of muscle movements, often as a result of cerebellar or spinocerebellar neurodegeneration. SK/IK channel modulators have been developed over the past few decades. Currently available modulators are often weak in potency. Lack of knowledge about the binding site for the compounds is the main reason hindering the development of more potent and effective therapeutics targeting SK channels. Dr. Zhang and his colleagues recently discovered the binding pocket for these positive modulators of SK/IK channels. This pocket is located at the interface between the channel and calmodulin. Dr. Zhang and his colleagues performed screening of a large number of compounds in silico, to find those fitting into the binding pocket. I performed electrophysiological recordings to evaluate the efficacy and the potency of these modulators on SK2 channels. We discovered a correlation between the total binding energy values calculated from the structures and the potencies determined from electrophysiological recording.</p>

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year

2018

Author dc:creator

• Orfali, Razan

Contributors dc:contributor

• Miao Zhang, Ph.D.
• Aftab Ahmed, Ph.D.
• Kamaljit Kaur, Ph.D.

• SK channel
• Ataxia
• Purkinje cells
• Positive allosteric modulator
• calmodulin
• interaction Energy
• Other Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/1

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_theses-1000