Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants
Open accessPublished version of a preprint
Abstract
Most treatments to alleviate major depression work by either inhibiting human monoamine transporters, vital for the reuptake of monoamine neurotransmitters, or by inhibiting monoamine oxidases, which are vital for their degradation. The analysis of the experimental 3D structures of those antidepressants in their drug formulation state is key to precision drug design and development. In this study, microcrystal electron diffraction (MicroED) is applied to reveal the atomic 3D structures for the first time of five of the most prevalent antidepressants (reboxetine, pipofezine, ansofaxine, phenelzine, and bifemelane) directly from the commercially available powder of the active ingredients. Their modes of binding are investigated by molecular docking, revealing the essential contacts and conformational changes into the biologically active state. This study underscores the combined use of MicroED and molecular docking to uncover elusive drug structures and mechanisms to aid in further drug development pipelines.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Binda, C., Wang, J., Li, M., Hubalek, F., Mattevi, A., & Edmondson, D. E. (2008) · Biochemistry · doi:10.1021/bi8002814 · Cited by 75 · see citing works
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- Authors
- Lin, J., Bu, G., Unge, J., & Gonen, T.
- Affiliations
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gonen, Tamir
- Venue
- Advanced Therapeutics
- Publisher
- Wiley
- Published
- 2024-07-31
- Volume
- 7
- Issue
- 9
- ISSN
- 2366-3987 (ISSN-L)
- PMC
- PMC11864751
- OpenAlex
- W4401178539
- Cited by
- 5
- References
- 2
- Citations by year
- 2026: 2 · 2025: 3
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Advanced Therapeutics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (P41GM136508)
- U.S. Department of Defense (MCDC‐2202‐002)
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- antidepressants, major depressive disorder, monoamine transporters, monoamine oxidase inhibition, reboxetine, phenelzine, bifemelane, microcrystal electron diffraction, molecular docking, drug binding mode
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