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Description

Purpose: Potassium-Chloride Cotransporter 2 (KCC2) is a neuronal membrane protein specific to the central nervous system. It is responsible for removing Cl- ions from the intracellular space, maintaining a normal Cl- gradient essential for proper function at inhibitory synapses. Dysregulation causes an upward shift in the Cl- reversal potential resulting in a hyperexcitable state of the postsynaptic neuron. Existing literature indicates that KCC2 may be involved in the addiction pathway of a variety of drugs of abuse, including opioids and alcohol. This makes KCC2 an attractive potential drug target when treating substance use disorders. A novel direct KCC2 agonist, VU0500469, was recently identified experimentally; however, no binding sites were identified or characterized. The goal of this project is to identify likely binding sites of this protein-ligand pair via computer simulation.

Methods: A 3D model of human KCC2 was obtained from RCSB Protein Databank. VU0500469 was reconstructed manually. Protein-ligand computational simulations were run using AutoDock Tools and AutoDock Vina, GNINA, and P2Rank to identify direct interactions between VU0500469, and KCC2.

Results: Results between simulations were then compared, and several possible VU0500469 binding pocket sites were successfully identified. We plan to further investigate molecular binding dynamics using CHARMM.

Conclusion: The binding sites identified may represent targets for the development of additional KCC2 agonists.

Disciplines

Amino Acids, Peptides, and Proteins | Laboratory and Basic Science Research | Molecular and Cellular Neuroscience | Molecular Biology | Pharmacology | Substance Abuse and Addiction

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In silico identification of small molecule agonist binding sites on KCC2

Purpose: Potassium-Chloride Cotransporter 2 (KCC2) is a neuronal membrane protein specific to the central nervous system. It is responsible for removing Cl- ions from the intracellular space, maintaining a normal Cl- gradient essential for proper function at inhibitory synapses. Dysregulation causes an upward shift in the Cl- reversal potential resulting in a hyperexcitable state of the postsynaptic neuron. Existing literature indicates that KCC2 may be involved in the addiction pathway of a variety of drugs of abuse, including opioids and alcohol. This makes KCC2 an attractive potential drug target when treating substance use disorders. A novel direct KCC2 agonist, VU0500469, was recently identified experimentally; however, no binding sites were identified or characterized. The goal of this project is to identify likely binding sites of this protein-ligand pair via computer simulation.

Methods: A 3D model of human KCC2 was obtained from RCSB Protein Databank. VU0500469 was reconstructed manually. Protein-ligand computational simulations were run using AutoDock Tools and AutoDock Vina, GNINA, and P2Rank to identify direct interactions between VU0500469, and KCC2.

Results: Results between simulations were then compared, and several possible VU0500469 binding pocket sites were successfully identified. We plan to further investigate molecular binding dynamics using CHARMM.

Conclusion: The binding sites identified may represent targets for the development of additional KCC2 agonists.