Identification of potential Phosphodiesterase 1 inhibitors from plant phytochemicals for the treatment of cognitive impairment using molecular modeling tools

Plants and their phytomolecules have been employed for centuries to treat various illnesses, including cognitive impairments. In modern drug discovery, phytomolecule libraries serve as an important source for identifying novel therapeutic agents, particularly for complex diseases, as de novo chemical synthesis is often time-consuming and expensive. In this study, a total of 44,085 Central Nervous System (CNS)-targeting phytomolecules were retrieved from the ChemDiv library and systematically screened for their potential as inhibitors of the phosphodiesterase-1 (PDE1) receptor using molecular modeling tools. PDE1 is a key enzyme predominantly expressed in brain tissues that hydrolyzes the 3’,5’-cAMP (3’,5’-cyclic Adenosine Monophosphate) and 3’,5’-cGMP (3’,5’-cyclic Guanosine Monophosphate) and into their inactive monophosphate counterparts, 5’-cAMP and 5’-cGMP. Cyclic nucleotides are essential for regulating neuronal signaling pathways. An initial molecular docking analysis identified 10 phytomolecules exhibiting strong binding affinities ranging from −11.97 to −12.54 kcal×mol −1 , and significant interactions with key amino acid residues within the active site of PDE1. Molecular dynamics simulations confirmed that four protein-ligand complexes (D361-0316-PDE1, L977-1068-PDE1, J081-0995-PDE1, and L977-1023-PDE1) remained structurally stable for up to 100 nanoseconds. Further, density functional theory (DFT) studies confirmed the electronic stability of these molecules. ADMET and drug-likeness evaluations predicted pharmacokinetics and toxicity profile. Overall, the findings suggest that these four phytomolecules may serve as promising PDE1 inhibitors for the management of cognitive impairment.