Exploring Alternative Binding Locations of 5-HT Antagonist Ketanserin In Microtubules; Implications for Future Research
Abstract
Recently, it’s been demonstrated that classic psychedelic action is mediated via intracellular mechanisms rather than action at membrane receptors. This intracellular action elicits neuroplastic effect. The conclusion is that these effects are due to activation of intracellular 5-HT2AR based on using ketanserin as a selective antagonist based on its selectivity to bind to the membrane 5-HT2A serotonin receptor. However, neuroplasticity is dependent upon multiple mechanisms and signaling cascades including the dynamics of neuronal microtubules. As the targets of ketanserin’s biological intracellular activity are not fully elucidated, here we investigate the binding potential of ketanserin to domains of the microtubule constituent protein tubulin. Autodock 4.2 was used to conduct molecular docking (MD) simulations within ketanserin to tubulin. Results show that ketanserin has a stronger binding affinity (-9.83 kcal/mol) and lower inhibition constant (62.32 nM) to the colchicine binding site of tubulin than colchicine itself (-9.78 kcal/mol and 67.74 nM); thereby necessitating reevaluation of conclusions based on ketanserin’s intracellular selectivity to the 5-HT2AR alone. Experimental microtubule polymerization assays with/without presence of ketanserin are ultimately needed to confirm these predictions. The results of this study may indicate that psychedelic activity is not solely based in the intracellular regulation of 5-HT2AR, but perhaps in microtubule dynamics as well. Further study is warranted.
Faculty Sponsors
Dr. Travis Craddock
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-3-2024 12:30 PM
End Date
4-4-2024 1:30 PM
Exploring Alternative Binding Locations of 5-HT Antagonist Ketanserin In Microtubules; Implications for Future Research
Alvin Sherman Library
Recently, it’s been demonstrated that classic psychedelic action is mediated via intracellular mechanisms rather than action at membrane receptors. This intracellular action elicits neuroplastic effect. The conclusion is that these effects are due to activation of intracellular 5-HT2AR based on using ketanserin as a selective antagonist based on its selectivity to bind to the membrane 5-HT2A serotonin receptor. However, neuroplasticity is dependent upon multiple mechanisms and signaling cascades including the dynamics of neuronal microtubules. As the targets of ketanserin’s biological intracellular activity are not fully elucidated, here we investigate the binding potential of ketanserin to domains of the microtubule constituent protein tubulin. Autodock 4.2 was used to conduct molecular docking (MD) simulations within ketanserin to tubulin. Results show that ketanserin has a stronger binding affinity (-9.83 kcal/mol) and lower inhibition constant (62.32 nM) to the colchicine binding site of tubulin than colchicine itself (-9.78 kcal/mol and 67.74 nM); thereby necessitating reevaluation of conclusions based on ketanserin’s intracellular selectivity to the 5-HT2AR alone. Experimental microtubule polymerization assays with/without presence of ketanserin are ultimately needed to confirm these predictions. The results of this study may indicate that psychedelic activity is not solely based in the intracellular regulation of 5-HT2AR, but perhaps in microtubule dynamics as well. Further study is warranted.
