title: 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.
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Molinski
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Vijay M
authors.initials: VM
authors.lastname: Shahani
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: MacKinnon
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Morayniss
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Marcon
authors.initials: M
authors.lastname: Laforet
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Woollard
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Naheed
authors.initials: N
authors.lastname: Kurji
authors.affiliation: Division of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Cecilia G
authors.initials: CG
authors.lastname: Sanchez
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada.
authors.forename: Shoshana J
authors.initials: SJ
authors.lastname: Wodak
authors.affiliation: Cyclica Inc., Toronto, Ontario, Canada. Electronic address: andreas.windemuth@cyclicarx.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Windemuth
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000700:Analgesics / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D019295:Computational Biology / Q000379:methods; D003497:Cyclic N-Oxides / Q000009:adverse effects* / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D062105:Molecular Docking Simulation; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D020543:Proteome / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000009:adverse effects* / Q000737:chemistry* / Q000493:pharmacokinetics; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000700:Analgesics; D003497:Cyclic N-Oxides; D020543:Proteome; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases; C000612073:BIA 10-2474
keywords: BIA 10-2474 (PubChem CID: 46831476); Bioinformatics; Drug-protein interactome; In silico polypharmacology; Neurotoxicity; Proteome-docking