Identification of PDE10A Binding Ligands as Potential Therapeutics for the Parkinson's Disease Through a Computational Approach

Parkinson’s disease is a neurodegenerative disease, causing dopamine depletion and resulting in physical and mental issues. The dopamine related treatments have been in use for a long time, they have not yet provided a complete cure, prompting the search for alternative therapeutic strategies. PDE10A is a dual-substrate phosphodiesterase highly expressed in the striatal medium spiny neurons, where it regulates dopamine-dependent signaling by hydrolyzing cAMP and cGMP. In Parkinson’s disease, dopamine depletion disrupts these cyclic nucleotide pathways, impairing motor control and neuronal function. Overactive PDE10A further reduces cAMP/cGMP levels, exacerbating motor deficits. Inhibiting PDE10A prolongs cyclic nucleotide signaling, potentially restoring balance between the direct and indirect basal ganglia pathways, improving motor function, and offering neuroprotective benefits—making it a promising therapeutic target for PD. Triazolopyridines have been reported as potent PDE10A inhibitors and were selected for in silico studies to build 3D QSAR model. The selected model is having a R2 and Q2 values of 0.9530 and 0.9671, respectively. Subsequently after conducting pharmacophore modelling, the AAHHHR_1 model having two hydrogen bond acceptors (A1, A2), three hydrophobic interactions (H5, H6, H9), and one aromatic ring (R13) was selected to screen NPASS database, a natural compound’s library, to find molecules with similar pharmacophore arrangements. After analysing molecular docking, MMGBSA and ADME, the top five hits were selected. These compounds exhibited docking scores ranging from –11.27 to –13.210 kcal/mol, outperforming the standard reference molecule (–9.204 kcal/mol). MM/GBSA binding free energy calculations further revealed comparable scores ranging from –59.60 to –68.75 kcal/mol for hits, compared to –71.67 kcal/mol for the standard. While MD studies confirmed the stability of hits with PDE10A forming favourable hydrogen bond interactions throughout a trajectory of 100ns. Lastly, MMPBSA showed that out of all the five hit molecules, NPASS_6815, NPASS_8727 and NPASS_31450 outperforms with binding free energy of -31.15, -22.05 and -23.07 kcal/mol while other molecules depicted comparable binding free energy in the range of -19.17 to -20.27 kcal/mol when compared to reference molecules (-21.26 kcal/mol). Based on these findings, the three molecules hold potential as PDE10A inhibitors and could serve as lead compounds for the development of new therapeutic agents for Parkinson’s disease.