People who endure depressive disorders suffer from ineffective medical treatment. Medicines that are prescribed to these patients often take weeks of regular administration to take effect, which are inconsistent and vary from person to person. Fortunately, there seems to be an effective alternative. Previous research has indicated that antagonistic binding of the human kappa opioid receptor (KOR) results in anti-depressant effects such as mood elevation. Because KOR antagonists target a different pathway from traditional anti-depressants, they offer potential benefits of being faster, more consistent, and without risk of addiction. Using computational techniques, this study seeks to develop a model of the KOR and design antagonists to interact with it. The KOR model is based on the crystal structure of antagonist JDTic bound to the human KOR-T4 lysozyme chimera (PDB ID: 4DJH). Using Schrodinger software, we remove the T4 lysozyme, corrected the mutations, and optimized the protein structure. We also use Sphinx loop predictor to generate missing and unresolved loops. The predicted structure is inserted into a solvated and neutralized lipid bilayer, and molecular dynamics are run with Desmond software to stabilize the complex. Then, we can perform virtual ligand screening with DockBlaster software to identify commercially-available compounds in the Zinc database that can bind to our model of KOR. A small subset of low-lying hits will be docked with Glide software to identify one or two promising candidates. These techniques will allow for the specific creation of potential drugs so that unfavorable interactions with off-target receptors causing side effects can be minimized. Through this method, this study will present novel antagonists that are specific to the KOR and are scaffolds for future anti-depressant medication.<br/>

Simulation of human-kappa opioid receptor antagonists to develop alternative anti-depressants

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.