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Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants
Open accessPreprint — published as 10.1002/adtp.202400117 · Paper page
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, we apply microcrystal electron diffraction (MicroED) to reveal the atomic 3D structures for the first time of five of the most prevalent antidepressants (reboxetine, pipofezine, ansofaxine, phenelzine, 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
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Research works printed but not linked: 47
- 10.1007/s00018-009-0055-x · DOI
- 2000, History and evolution of the monoamine hypothesis of depression, J. Clin. Psychiatry, 61, 4
- 10.4088/JCP.v61n0103 · DOI
- 2017, Overview of monoamine transporters, Curr. Protoc. Pharmacol, 79, 12
- 1999, Role of MAO A and B in neurotransmitter metabolism and behavior, Pol. J. Pharmacol, 51, 25
- 10.1016/S0006-3223(99)00291-7 · DOI
- 2004, The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile, CNS Drug Rev, 10, 23, 10.1111/j.1527-3458.2004.tb00002.x · DOI
- 2009, Comparison of antidepressant effects of azafan, tianeptine, and paroxetine, Bull. Exp. Biol. Med, 148, 54, 10.1007/s10517-009-0638-4 · DOI
- 1969, The pharmacologic properties and therapeutic effectiveness of the new antidepressant preparation Azaphen, Zh Nevrol Psikhiatr Im S S Korsakova, 69, 1234
- 2022, Efficacy, safety, and tolerability of ansofaxine (LY03005) extended-release tablet for major depressive disorder: a randomized, double-blind, placebo-controlled, dose-finding, phase 2 clinical trial, Int. J. Neuropsychopharmacol, 25, 252, 10.1093/ijnp/pyab074 · DOI
- 2020, Parameters for irreversible inactivation of monoamine oxidase, Molecules, 25, 5908, 10.3390/molecules25245908 · DOI
- 10.1001/jama.1961.73040340018012 · DOI
- 1988, 4-(O-benzylphenoxy)-N-methylbutylamine (bifemelane) and other 4-(O-benzylphenoxy)-N-methylalkylamines as new inhibitors of type A and B monoamine oxidase, J. Neurochem, 50, 243, 10.1111/j.1471-4159.1988.tb13256.x · DOI
- 1995, Effects of bifemelane hydrochloride on plasma neuropeptide Y, 3-methoxy-4-hydroxyphenylethylene glycol and 5-hydroxy-indole acetic acid concentrations in patients with cerebral infarction, Drugs Exp. Clin. Res, 21, 175
- 2009, Polytypism in desvenlafaxine succinate monohydrate, CrystEngComm, 11, 989, 10.1039/b821274k · DOI
- 1990, Structure du chlorure d’[(éthoxy-2 phénoxy) méthyl]-2 morpholinium: chlorhydrate de viloxazine, Acta Crystallogr. C, 46, 2160, 10.1107/S0108270190001627 · DOI
- Diederichs, K. & Wang, M. Serial synchrotron X-ray crystallography (SSX). Protein Crystallography: Methods and Protocols, 239–272 (2017). · DOI
- 2001, Contemporary advances in the use of powder X-ray diffraction for structure determination, Angew. Chem. Int, 40, 1626, 10.1002/1521-3773(20010504)40:9<1626::AID-ANIE16260>3.0.CO;2-7 · DOI
- 2023, Atomic-level structure determination of amorphous molecular solids by NMR, Nat. Commun, 14, 5138, 10.1038/s41467-023-40853-2 · DOI
- 2022, De novo crystal structure determination from machine learned chemical shifts, J. Am. Chem. Soc, 144, 7215, 10.1021/jacs.1c13733 · DOI
- 10.7554/eLife.01345 · DOI
- 10.1038/nmeth.3043 · DOI
- 2018, The CryoEM method MicroED as a powerful tool for small molecule structure determination, ACS Cent. Sci, 4, 1587, 10.1021/acscentsci.8b00760 · DOI
- Karothu, D. P. et al. The Elusive Structure of Levocetirizine Dihydrochloride Determined by Electron Diffraction. Angew. Chem. Int. Ed. e202303761 (2023). · DOI
- Lin, J. , Unge, J. & Gonen, T. Unraveling the Structure of Meclizine Dihydrochloride with MicroED. bioRxiv, 2023–2009 (2023). · DOI
- 2023, MicroED as a powerful tool for structure determination of macrocyclic drug compounds directly from their powder formulations, ACS Chem. Biol, 18, 2582, 10.1021/acschembio.3c00611 · DOI
- Bu, G. , Danelius, E. , Wieske, L. & Gonen, T. Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED. bioRxiv, 2023–2009 (2023). · DOI
- Smith, S. M. Strategies for the purification of membrane proteins. Protein Chromatography: Methods and Protocols, 389–400 (2017). · DOI
- 10.1038/nsmb.3029 · DOI
- 10.1038/nsmb.1602 · DOI
- 10.1038/nature17629 · DOI
- 10.1073/pnas.0710626105 · DOI
- 10.1073/pnas.1633804100 · DOI
- 10.1107/S2052252519010583 · DOI
- 10.1107/S0907444909047337 · DOI · Paper page
- 10.1107/S0907444909047374 · DOI
- 2015, SHELXT–Integrated space-group and crystal-structure determination, Acta Crystallogr. A, 71, 3, 10.1107/S2053273314026370 · DOI · Paper page
- 10.1107/S0907444902011678 · DOI
- 10.1107/S0108767307043930 · DOI
- 10.1107/S0021889811043202 · DOI
- 10.1021/acs.jcim.1c00075 · DOI
- 10.1021/bi8002814 · DOI · Paper page
- 10.1002/jcc.21334 · DOI · Paper page
- 10.1021/acs.jcim.1c00203 · DOI
- 2015, The PyMOL molecular graphics system, Version, 1, 8
- 2022, CB-Dock2: Improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting, Nucleic Acids Res, 50, W159, 10.1093/nar/gkac394 · DOI
- 10.1093/NAR/GKAB294 · DOI
Metadata
- 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
- openRxiv
- Published
- 2024-01-05
- Volume
- 7
- Issue
- 9
- ISSN
- 2366-3987 (ISSN-L)
- PMC
- PMC11864751
- OpenAlex
- W4401178539
- Cited by
- 5
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- 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
- U.S. Department of Defense (MCDC‐2202‐002, W15QKN-16-9-1002)
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of General Medical Sciences (P41GM136508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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