In silico identification of novel ligands targeting stress-related human FKBP5 protein in mental disorders.

FK506-binding protein 51 (FKBP51 or FKBP5) serves as a crucial stress modulator implicated in mental disorders, presenting a potential target for intervention. Inhibitors like SAFit2, rapamycin, and tacrolimus exhibit promising interactions with this protein. Despite these advances, challenges persist in diversifying FKBP5 ligands, prompting further exploration of interaction partners. Hence, this study aims to identify other potential ligands. Employing molecular docking, we generated complexes with various ligands (rapamycin, tacrolimus, SAFit2-Selective antagonist of FKBP51 by induced fit, ascomycin, pimecrolimus, rosavin, salidroside, curcumin, apigenin, uvaricin, ruscogenin, neoruscogenin, pumicalagin, castalagin, and grandinin). We identified the top 3 best ligands, of which ruscogenin and neoruscogenin had notable abilities to cross the blood-brain barrier and have high gastrointestinal absorption, like curcumin. Toxicity predictions show ruscogenin and neoruscogenin to be the least toxic based on oral toxicity classification (Class VI). Tyrosine (Tyr113) formed consistent interactions with all ligands in the complex, reinforcing their potential and involvement in stress modulation. Molecular dynamic (MD) simulation validated strong interactions between our three key ligands and FKBP5 protein and provided an understanding of the stability of the complex. The binding free energy (ΔG) of the best ligands (based on pharmacological properties) from MD simulation analysis is -31.78 kcal/mol for neoruscogenin, -30.41 kcal/mol for ruscogenin, and -27.6 kcal/mol for curcumin. These molecules, therefore, can serve as therapeutic molecules or biomarkers for research in stress-impacted mental disorders. While offering therapeutic implications for mental disorders by attenuating stress impact, it is crucial to emphasize that these ligands' transition to clinical applications necessitates extensive experimental research, including clinical trials, to unravel the intricate molecular and neural pathways involved in these interactions.