Molecular mechanisms involved in the side effects of fatty acid amide hydrolase inhibitors: a structural phenomics approach to proteome-wide cellular off-target deconvolution and disease association.

Fatty acid amide hydrolase (FAAH) is a promising therapeutic target for the treatment of pain and CNS disorders. However, the development of potent and safe FAAH inhibitors is hindered by their off-target mediated side effect that leads to brain cell death. Its physiological off-targets and their associations with phenotypes may not be characterized using existing experimental and computational techniques as these methods fail to have sufficient proteome coverage and/or ignore native biological assemblies (BAs; i.e., protein quaternary structures). To understand the mechanisms of the side effects from FAAH inhibitors and other drugs, we develop a novel structural phenomics approach to identifying the physiological off-targets binding profile in the cellular context and on a structural proteome scale, and investigate the roles of these off-targets in impacting human physiology and pathology using text mining-based phenomics analysis. Using this integrative approach, we discover that FAAH inhibitors may bind to the dimerization interface of NMDA receptor (NMDAR) and several other BAs, and thus disrupt their cellular functions. Specifically, the malfunction of the NMDAR is associated with a wide spectrum of brain disorders that are directly related to the observed side effects of FAAH inhibitors. This finding is consistent with the existing literature, and provides testable hypotheses for investigating the molecular origin of the side effects of FAAH inhibitors. Thus, the method proposed here, which can for the first time predict proteome-wide drug interactions with cellular BAs and link BA-ligand interaction with clinical outcomes, can be valuable in off-target screening. The development and application of such methods will accelerate the development of more safe and effective therapeutics.