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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
A novel small molecule inhibitor of human Drp1
Ayeshah A Rosdah1,2,3, Belinda M Abbott4, Christopher G Langendorf1
1St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
Abstract:
Mitochondrial dynamin-related protein 1 (Drp1) is a large GTPase regulator of mitochondrial dynamics and is known to play an important role in numerous pathophysiological processes. Despite being the most widely used Drp1 inhibitor, the specificity of Mdivi-1 towards human Drp1 has not been definitively proven and there have been numerous issues reported with its use including off-target effects. In our hands Mdivi-1 showed varying binding affinities toward human Drp1, potentially impacted by compound aggregation. Herein, we sought to identify a novel small molecule inhibitor of Drp1. From an initial virtual screening, we identified DRP1i27 as a compound which directly bound to the human isoform 3 of Drp1 via surface plasmon resonance and microscale thermophoresis. Importantly, DRP1i27 was found to have a dose-dependent increase in the cellular networks of fused mitochondria but had no effect in Drp1 knock-out cells. Further analogues of this compound were identified and screened, though none displayed greater affinity to human Drp1 isoform 3 than DRP1i27. To date, this is the first small molecule inhibitor shown to directly bind to human Drp1.
Insights
Researchers identified DRP1i27, a novel small molecule inhibitor that directly binds to human dynamin-related protein 1 (Drp1). This compound promotes mitochondrial fusion, offering a specific tool for studying Drp1 in disease.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Mitochondrial dynamics are regulated by dynamin-related protein 1 (Drp1), a GTPase implicated in various pathophysiological processes.
- The widely used Drp1 inhibitor Mdivi-1 lacks proven specificity for human Drp1 and exhibits off-target effects, necessitating the development of novel inhibitors.
Purpose of the Study:
- To identify and characterize a novel small molecule inhibitor that directly targets human Drp1.
- To evaluate the specificity and cellular effects of the identified inhibitor.
Main Methods:
- Virtual screening was employed to identify potential Drp1 inhibitors.
- Surface plasmon resonance and microscale thermophoresis were used to confirm direct binding of DRP1i27 to human Drp1 isoform 3.
- Cellular assays were performed in Drp1 knock-out cells to assess the compound's specificity and effects on mitochondrial morphology.
Main Results:
- DRP1i27 was identified as a novel small molecule that directly binds to human Drp1 isoform 3.
- DRP1i27 demonstrated a dose-dependent increase in fused mitochondrial networks in cells.
- The observed effects of DRP1i27 were absent in Drp1 knock-out cells, confirming its specificity.
- No analogues of DRP1i27 showed greater binding affinity to human Drp1 isoform 3.
Conclusions:
- DRP1i27 is the first small molecule inhibitor demonstrated to directly bind to human Drp1.
- This compound represents a specific and valuable tool for investigating the role of Drp1 in cellular processes and disease states.
- The findings highlight the potential for developing targeted Drp1 inhibitors with improved specificity over existing agents.
