Exploring the mechanisms and properties of Auvelity through computational chemistry

Jensen, Anna Rosenbak

4. Term

Chemistry, Master (polyt)

2024

2024-06-02

47

Denne afhandling undersøgte, hvor og hvordan lægemidlet Auvelity, en kombination af dextromethorphan og bupropion, binder til og påvirker NMDA-receptoren. NMDA-receptoren er et protein på nerveceller, der medvirker til signaloverførsel i hjernen. Arbejdet fokuserede på dextromethorphan, som fungerer som en antagonist (et stof der dæmper receptorens aktivitet). Vi brugte computerbaserede metoder: molekylær docking til at forudsige, hvordan stoffet passer i receptoren, molekylære dynamik-simuleringer for at se bevægelser over tid, og MM-GBSA-energiberegninger for at estimere bindingsstyrken. Analyserne viste, at dextromethorphan binder i receptorens aminoterminale domæne (en ydre region) med en beregnet bindingsaffinitet på −10.2 kcal/mole. De vigtigste kræfter bag bindingen var van der Waals-interaktioner, suppleret af elektrostatiske kræfter. Vi sammenlignede med ketamin, en velkendt antagonist, og fandt tilsvarende bindingsstyrke og interaktionskræfter. Simulationerne indikerede også, at ketamin binder i det aminoterminale domæne. Samlet peger resultaterne på, at både dextromethorphan og ketamin regulerer NMDA-receptoren via allosterisk modulation, dvs. ved at påvirke receptoren ved at binde et andet sted end det centrale aktiveringssted.

This thesis investigated where and how the medicine Auvelity, a combination of dextromethorphan and bupropion, binds to and affects the NMDA receptor. The NMDA receptor is a protein on nerve cells that helps control brain signaling. The study focused on dextromethorphan, which acts as an antagonist (a molecule that reduces receptor activity). We used computer-based methods: molecular docking to predict how the molecule fits in the receptor, molecular dynamics simulations to track motions over time, and MM-GBSA energy calculations to estimate binding strength. The analyses indicate that dextromethorphan binds to the receptor's amino-terminal domain (an outer region) with a predicted binding affinity of −10.2 kcal/mole. The binding was driven mainly by van der Waals interactions, supported by electrostatic forces. We compared these findings with ketamine, a well-known antagonist, and observed similar binding strength and interaction patterns. The simulations also predicted that ketamine binds to the amino-terminal domain. Together, these results suggest that both dextromethorphan and ketamine regulate the NMDA receptor through allosteric modulation, meaning they alter receptor activity by binding at a site separate from the main activation site.

[This summary has been rewritten with the help of AI based on the project's original abstract]

Auvelity ; DXM ; Ketamin ; MM/GBSA ; MD-simulationer ; Depression

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