Enhanced sampling simulations to explore himalayan phytochemicals as potential phosphodiesterase-1 inhibitor for...

The rising incidence of neurological and neuropsychiatric disorders underscores the urgent need for innovative and evidence based treatment strategies. Phosphodiesterase-1 (PDE1) is a dual-substrate (cAMP/cGMP) phosphodiesterase expressed in the central nervous system and peripheral areas, which modulates cyclic nucleotide signaling cascades. Inhibiting PDE1 enhances cAMP/cGMP levels, promoting neuronal plasticity and neuroprotection, making it a promising therapeutic strategy for neurological disorders. The pursuit of targeting this enzyme for treating neurological and neuropsychiatric disorders has faced obstacles due to the absence of potent, selective, and brain-penetrating inhibitors. This study aimed to identify potent PDE1 inhibitors by leveraging a diverse collection of bioactive molecules derived from Himalayan flora through computational screening methods. The four most promising hit molecules were chosen for further investigation and subjected to Molecular Dynamics (MD) simulations, binding free energy calculations, along with standard molecules. It was found that the hit molecules stigmast-7, corilagin and emblicanin-A had formed the most stable complexes, and also, the least binding free energy was observed for stigmast-7 among the hit molecules. Additionally, the pulling simulations indicated that stigmast-7 and corilagin were the most robust binders, and required the highest force to dissociate from the binding cavity completely. The umbrella sampling simulations also revealed the lowest binding free energy for corilagin and stigmast-7. The insights gained from this study provide a foundation for future research into PDE1-targeted therapies, highlighting the potential of Himalayan bioactive compounds in developing novel therapeutic interventions.