FKBP5 blockade may provide a new horizon for the treatment of stress‐associated disorders: An in‐silico study

Abstract

Objective We searched for, from the FDA (Food and Drug Administration‐USA)‐approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio‐informatics tools (in‐silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress‐associated disorders. Methods Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene‐chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, http://clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)]. Results After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability. Significance While the current in‐silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress‐associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.

“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”

“…Ponatinib is used to treat chronic myeloid leukemia. In an in-silico study, ponatinib was suggested for the treatment of functional seizures 86 , and it also reduced seizure severity in a kainate-induced status epilepticus rat model 87 .…”

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery

“…The drugs discussed in this section are the most promising drugs that can inhibit the FKBP51 protein based on our previous in-silico study. In a previous study, multiple databases were screened, and those therapeutics that can cross the blood-brain barrier (BBB) and have capable pharmacologic and bioinformatic features for interacting with and inhibiting the FKBP5 gene were reported (43). In addition, the effects of different drugs on FKBP51 are listed in Table 3.…”

“…Recently, an association between mutations of FKBP5 and functional seizures, another stress-induced disease whose biological aspects are not well known, has been found (41,42). Moreover, in another study, potential drugs for targeting the FKBP51 protein have been investigated and reported (43) because the inhibition of FKBP51 can promote the regulation of the HPA axis in stress-induced disorders (41,43). In this study, we attempted to explain the role of FKBP5 in the human body, especially in the HPA axis and stress-induced disorders, the effects of the most important genetic mutations of this gene in stress-induced disorders, and the potential therapeutic effects affecting FKBP51.…”