In-silico discovery of dual active molecule to restore synaptic wiring against autism spectrum disorder via HDAC2 and H3R inhibition

Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2’s differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico. The importance of ligand contacts with the Zn(2+) ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.