The Antidepressant Drug Clomipramine Inhibits the ABC Transporter BmrA

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Epithelial barriers like the intestine and blood-brain barrier limit drug uptake via efflux pumps such as ABCB1.
• Developing central nervous system drugs often necessitates co-administration of efflux inhibitors.
• Studying human ABCB1 inhibitors is difficult due to limited protein availability.

Purpose of the Study:

• Investigate the mechanism of clomipramine, an antidepressant, in reducing multidrug resistance.
• Explore the potential of bacterial ABC transporters, like BmrA, as models for studying human ABCB1 inhibitors.
• Identify clomipramine binding sites on BmrA and their conservation in human ABCB1.

Main Methods:

• Assessed clomipramine's effect on the ATPase activity of full-length BmrA and its nucleotide-binding domain.
• Utilized binding assays to identify clomipramine binding sites on BmrA.
• Employed molecular modeling to predict and visualize binding interactions.
• Compared identified binding sites with those in human ABCB1.

Main Results:

• Clomipramine was found to inhibit the ATPase activity of both full-length BmrA and its isolated nucleotide-binding domain.
• Multiple clomipramine binding sites were identified on BmrA.
• These binding sites, including one overlapping the ATP-binding pocket, are conserved in human ABCB1.
• The findings suggest a potential mechanism for clomipramine's effect on ABC transporters.

Conclusions:

• Clomipramine's inhibition of BmrA ATPase activity indicates potential side effects related to ABC transporter function.
• Bacterial ABC transporters like BmrA serve as valuable models for studying inhibitors when human protein studies are challenging.
• This research provides insights into clomipramine's interaction with ABC transporters and validates the use of bacterial systems for drug discovery and safety assessments.