Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Ye Han; Kyle A. Lyman; Matt Clutter; Gary E. Schiltz; Quratul-Ain Ismail; Xiangying Cheng; Chi-Hao Luan; Dane M. Chetkovich

doi:10.3791/54540

Procédé pour l'identification d'inhibiteurs de petites molécules de l'interaction pro...

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Biochemistry

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JoVE Journal Biochemistry

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Procédé pour l'identification d'inhibiteurs de petites molécules de l'interaction protéine-protéine entre HCN1 et TRIP8b

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10:20 min

November 11, 2016

DOI: 10.3791/54540-v

Ye Han*¹, Kyle A. Lyman*¹, Matt Clutter², Gary E. Schiltz³, Quratul-Ain Ismail¹, Xiangying Cheng¹, Chi-Hao Luan⁴, Dane M. Chetkovich^1,5

¹Davee Department of Neurology and Clinical Neurosciences,Feinberg School of Medicine, Northwestern University, ²Center for Molecular Innovation and Drug Discovery,Northwestern University, ³Department of Pharmacology,Feinberg School of Medicine, Northwestern University, ⁴High Throughput Analysis Laboratory, Department of Molecular Biosciences,Northwestern University, ⁵Department of Physiology,Feinberg School of Medicine, Northwestern University

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Overview

This article presents a fluorescence polarization-based method for identifying small molecule inhibitors that disrupt the interaction between TRIP8b and HCN channels. This approach aims to develop new treatments for Major Depressive Disorder and potentially other disorders such as chronic pain.

Key Study Components

Area of Science

Neuroscience
Pharmacology
Therapeutics

Background

HCN channels and their auxiliary subunit TRIP8b are implicated in Major Depressive Disorder.
Disrupting the TRIP8b-HCN interaction may offer therapeutic benefits.
This method can be performed in a high throughput manner.
Visual demonstrations enhance understanding of automated high throughput techniques.

Purpose of Study

To identify small molecules that inhibit the TRIP8b-HCN interaction.
To explore potential new treatments for depression.
To assess the method's applicability to other disorders.

Methods Used

Fluorescence polarization-based screening.
High throughput analysis.
Automated instrumentation.
Visual protocol demonstration.

Main Results

Identification of candidate small molecules for further development.
Demonstration of the method's efficiency in a high throughput setting.
Potential therapeutic implications for depression and chronic pain.
Support for the role of TRIP8b in HCN channel modulation.

Conclusions

The method shows promise for discovering new depression treatments.
Disruption of TRIP8b-HCN interactions may benefit other conditions.
Automated high throughput techniques can advance research.

Frequently Asked Questions

What is the main goal of this study?

The main goal is to identify small molecules that disrupt the TRIP8b-HCN channel interaction, potentially leading to new treatments for depression.

How does the method work?

The method utilizes fluorescence polarization to screen for small molecule inhibitors in a high throughput manner.

What are the implications of this research?

This research may lead to novel therapies for Major Depressive Disorder and other related disorders.

Why is high throughput analysis important?

High throughput analysis allows for the rapid screening of many compounds, increasing the efficiency of drug discovery.

What other disorders could benefit from this research?

In addition to depression, disrupting the TRIP8b-HCN interaction may also have therapeutic benefits for chronic pain.

Where was this research conducted?

The research was conducted at Northwestern University's high throughput analysis lab.

L'interaction entre les canaux HCN et leur sous-unité auxiliaire a été identifié comme une cible thérapeutique dans le trouble dépressif majeur. Ici, une méthode basée sur la polarisation de fluorescence pour identifier les petites molécules inhibitrices de cette interaction protéine-protéine, est présentée.

L’objectif global de cette procédure est d’identifier de petites molécules capables de perturber l’interaction entre les canaux TRIP8b et HCN. Cette méthode identifie des molécules candidates qui pourraient être développées dans de nouveaux traitements pour la dépression. Le principal avantage de cette technique est qu’elle peut être réalisée à haut débit.

Cette technique a des implications pour le développement d’un nouveau traitement pour le trouble dépressif majeur, car notre laboratoire a montré que la perturbation de la liaison de TRIP8b au HCN peut être bénéfique sur le plan thérapeutique. Bien que cette méthode ait été développée en tenant compte de la dépression, la perturbation de l’interaction entre TRIP8b et HCN peut être bénéfique sur le plan thérapeutique dans d’autres troubles tels que la douleur chronique. La démonstration visuelle de ce protocole est importante car elle illustre les avantages de l’utilisation d’instruments automatisés à haut débit pour faire progresser la recherche fondamentale et translationnelle dans des installations ouvertes comme le laboratoire d’analyse à haut débit de l’Université Northwestern.

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