Computational approaches for the identification of potential HDAC2 inhibitors and histamine H3 receptor antagonists from Berberis vulgaris : a dual mechanistic approach for autism spectrum disorder treatment

Abstract Autism spectrum disorder (ASD) encompasses early emerging deficits in repetitive sensory-motor behaviors and social communication. Rooted in a solid genetic foundation, ASD exhibits diversity among individuals but consistently manifests core features in restricted repetitive behaviors and social communication. ASD originates from early neural reorganization and alterations in brain development, forming a spectrum from mild to severe. The economic burden of ASD is substantial, driven by the ongoing need for assistance in adulthood. Histone deacetylase (HDAC) modulation, including HDAC2, influences ASD traits. Interest in HDAC modulation has led to the FDA approval of drugs that show promise. Additionally, studies suggest histamine, a CNS neurotransmitter, and H3R antagonism may impact social behavior in ASD. Recognizing the significance of HDAC2 and H3R, we conducted virtual screening of phytocompounds from Berberis vulgaris against these ASD-associated targets. Cinnamyl acetate (CA) emerged as the primary compound for targeting ASD. Molecular dynamics simulations were conducted to explore the dynamics and stability. Of the tested compounds, only three exhibited AMES toxicity, and none were predicted to be hERG I inhibitors or to cause oral acute toxicity in rats. The interaction energies for CA docking to HDAC2 and H3R were −7.4 and −7.6 kcal/mol, respectively. The molecular dynamics simulation confirmed the stability of CA with target proteins under physiological conditions, revealing minimal perturbation to the proteins’ secondary structure upon CA binding. These findings underscore the potential of CA in the treatment of ASD. The proposed inhibitor demonstrated dual-target activity, inhibiting HDAC2-mediated deacetylation and H3R-mediated synaptic transmission irregularity. Experimental validation is warranted to develop it as an effective drug against ASD.