In silico study of PDE10A inhibitors for schizophrenia disease: Molecular docking, ADMET and DFT analysis

Recently, interest in phosphodiesterase 10A inhibitors has increased for schizophrenia treatment. Medicinal chemists have extensively worked on developing potent PDE10A inhibitors with minimal side effects. However, despite these efforts, PDE10A inhibitors have yet to gain approval for treating neurodegenerative disorders, possibly due to limited research in this area. In this study, we used an in-silico approach to evaluate 100 novel compounds derived from pyrazine, quinazoline, triazine, hydrazone, and cinnoline for their interaction with the PDE10A receptor (PDB ID: 3HQY) through molecular docking. Based on their drug-like properties, including physicochemical characteristics and ADMET profiles, eight top-ranking compounds, comparable to the standard drug PF6, were selected. We further narrowed this down to six highly promising molecules and identified protein targets for the PDE10A compound using a target prediction tool. Further investigations, including FMO (Frontier Molecular Orbital) and MEP (Molecular Electrostatic Potential) studies, showed increased stability in the drug complexes due to a larger HOMO-LUMO gap. Additionally, a significant electrophilicity index indicated favorable electrophilic behavior and increased reactivity of the drugs. Overall, a detailed examination has identified new favorable sites for bond formation in the 6 anticipated analogs, suggesting their potential drugs for treating schizophrenia diseases.