Exploration of the Dual Action of Pyranopyrazoles as Anti‐Alzheimer Agents and Dopamine D2 Receptor Antagonist Through Molecular Docking, ADMET, DFT Calculations, and MD Simulations
Anjali Rani, M. Aslam, Javed Rabbani Khan, Garima Pandey, Kamlesh Kumari, Bhaskara Nand · ChemistrySelect · 2025
Abstract Pyranopyrazole derivatives have shown a wide range of biological properties, and their ability to modulate various biological pathways makes them promising candidates for action against various diseases. In this study, 47 pyranopyrazole‐based compounds were designed and subjected to comprehensive computational analysis to evaluate their potential biological activity. These compounds were structurally classified into two main series based on the ester substituent (R 2 = Et or Me) and the nature of R 1 (H or Ph). Their physicochemical parameters, such as dipole moment, aqueous solubility, and lipophilicity, were systematically assessed. This study investigates the use of pyranopyrazole derivatives as prospective therapeutic candidates that can work against both Alzheimer's disease and as dopamine D2 receptor antagonists. Also, a comparison with market‐available drugs risperidone and donepezil was done. Molecular docking showed that the molecules CMPD19 (−117.04 kcal/mol) for the D2 receptor and CMPD33 (−126.722 kcal/mol) for acetylcholinesterase have minimum binding energy. From ADMET studies, it was found that these CMPD demonstrate good water solubility and gastrointestinal absorption. DFT calculations were further done to obtain the optimized geometry and dipole moment of these CMPD. Both compounds CMPD19 and CMPD33 have a dipole moment of more than eight. Molecular dynamics (MD) simulations further confirmed more stability of these complexes formed for CMPD19 and CMPD33 compared to risperidone and donepezil, respectively. Further, MM‐PBSA analysis supported these findings by revealing more favorable binding free energies for CMPD19 and CMPD33.