Computational proteome-wide screening predicts neurotoxic drug-protein interactome for the investigational analgesic BIA 10-2474
Abstract
The investigational compound BIA 10-2474, designed as a long-acting and reversible inhibitor of fatty acid amide hydrolase for the treatment of neuropathic pain, led to the death of one participant and hospitalization of five others due to intracranial hemorrhage in a Phase I clinical trial. Putative off-target activities of BIA 10-2474 have been suggested to be major contributing factors to the observed neurotoxicity in humans, motivating our study's proteome-wide screening approach to investigate its polypharmacology. Accordingly, we performed an in silico screen against 80,923 protein structures reported in the Protein Data Bank. The resulting list of 284 unique human interactors was further refined using target-disease association analyses to a subset of proteins previously linked to neurological, intracranial, inflammatory, hemorrhagic or clotting processes and/or diseases. Eleven proteins were identified as potential targets of BIA 10-2474, and the two highest-scoring proteins, Factor VII and thrombin, both essential blood-clotting factors, were predicted to be inhibited by BIA 10-2474 and suggest a plausible mechanism of toxicity. Once this small molecule becomes commercially available, future studies will be conducted to evaluate the predicted inhibitory effect of BIA 10-2474 on blood clot formation specifically in the brain.
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The FAAH inhibitor BIA-102474-101 has a multitude of off-targets, including inhibition of essential blood-clotting factors thrombin and Factor VII.
“In light of the death and adverse events in other subjects given repeated high doses of the FAAH inhibitor BIA-102474-101 in a clinical trial (Kerbrat et al, 2016), it is crucial to note that this drug has multitude of off-targets, including inhibition of essential blood-clotting factors thrombin and Factor VII (van Esbroeck et al, 2017;Molinski et al, 2017), which may contributed to its toxicity.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Molinski et al, 2017
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- Authors
- Molinski, S. V., Shahani, V. M., MacKinnon, S. S., Morayniss, L. D., Laforet, M., Woollard, G., Kurji, N., Sanchez, C. G., Wodak, S. J., & Windemuth, A.
- Corresponding author
- Windemuth, Andreas
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 483
- Issue
- 1
- Pages
- 502-508
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2561790043
- Cited by
- 17
- References
- 32
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 5
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Toronto
- National Institute of General Medical Sciences (P20GM103629)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- neurotoxicity, polypharmacology, fatty acid amide hydrolase inhibitors, neuropathic pain, intracranial hemorrhage, factor VII, thrombin, coagulation, protein-protein interaction, drug safety
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Analgesics, Cyclic N-Oxides, Humans, Pyridines, Computational Biology, Neurotoxicity Syndromes, Proteome, Molecular Docking Simulation
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