Bhattacharya Kunal, Bhattacharjee Atanu, Chakraborty Manodeep, Das Dibyajyoti, Paudel Keshav Raj
Royal School of Pharmacy, The Assam Royal Global University, Guwahati, India.
Department of Pharmaceutical Chemistry, Pratiksha Institute of Pharmaceutical Sciences, Guwahati, India.
J Comput Chem. 2025 Jan 15;46(2):e70029. doi: 10.1002/jcc.70029.
Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions. Molecular dynamics simulations confirmed that the fluspirilene-PDE5 complex is stable and maintains its structural integrity over time. Binding energy calculations further highlighted favorable interactions, indicating that the drug forms a strong and stable bond with PDE5. Additional analyses, including studies of protein dynamics and energy landscape mapping, revealed how the drug interacts dynamically with PDE5, adapting to different conformations and maintaining stability. These findings suggest that fluspirilene may modulate PDE5 activity, potentially offering therapeutic benefits for Alzheimer's disease. This study provides strong evidence for repurposing fluspirilene as a treatment for Alzheimer's and lays the foundation for further experimental and clinical investigations.
