Computational proteome-wide screening predicts neurotoxic drug-protein interactome for the investigational analgesic BIA 10-2474

• Published in: Biochemical and biophysical research communications 2017-01, Vol.483 (1), p.502-508
• Main Authors: Molinski, Steven V., Shahani, Vijay M., MacKinnon, Stephen S., Morayniss, Leonard D., Laforet, Marcon, Woollard, Geoffrey, Kurji, Naheed, Sanchez, Cecilia G., Wodak, Shoshana J., Windemuth, Andreas
• Format: Article
• Language: English
• Subjects: Amidohydrolases - metabolism; Analgesics - adverse effects; Analgesics - chemistry; Analgesics - pharmacokinetics; BIA 10-2474 (PubChem CID: 46831476); Bioinformatics; Computational Biology - methods; Cyclic N-Oxides - adverse effects; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacokinetics; Drug-protein interactome; Humans; In silico polypharmacology; Molecular Docking Simulation; Neurotoxicity; Neurotoxicity Syndromes - metabolism; Proteome - chemistry; Proteome - metabolism; Proteome-docking; Pyridines - adverse effects; Pyridines - chemistry; Pyridines - pharmacokinetics
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.12.115

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. [Display omitted] •Polypharmacology of FAAH inhibitor BIA 10-2474 evaluated by in silico proteome-wide screening.•Identification of putative targets-of-action of BIA 10-2474 causing neurotoxicity.•Inhibition of factor VII and thrombin predicted to cause intracranial hemorrhaging.