What question did this study set out to answer?

The aim is to identify PDE10A binding ligands for the treatment of Parkinson's disease through computational methods.

July 11, 2026Open Access

Identification of PDE10A binding ligands as potential therapeutics for the Parkinson’s disease through a computational approach

BDBharti DeviCentral University of Punjab FNFathima NuzhaCentral University of Punjab KJKailash JangidCentral University of Punjab

Key Points

The aim is to identify PDE10A binding ligands for the treatment of Parkinson's disease through computational methods.
In silico studies using 3D QSAR model and pharmacophore modelling to select compounds.
Molecular docking, MMGBSA, and ADME analysis to evaluate top hits.
Molecular dynamics studies confirmed binding stability over a 200 ns trajectory.
Top five compounds identified with docking scores between -11.27 and -13.210 kcal/mol.
MM/GBSA calculations showed binding free energy for hits ranging from -59.60 to -68.75 kcal/mol, compared to the reference (-71.67 kcal/mol).
Complex NPASS_6815 displayed superior binding free energy of -30.26 kcal/mol against a reference of -23.38 kcal/mol.

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons and resulting in physical and mental issues. Dopamine-based treatments have long been used for Parkinson’s disease; however, they do not provide a complete cure, highlighting the need for alternative therapeutic strategies. Phosphodiesterase-10 A (PDE10A), a dual-substrate enzyme regulates dopamine signalling by hydrolyzing cAMP and cGMP. In PD, dopamine depletion disrupts cyclic nucleotide signalling, impairing motor function and overactived PDE10A further reduces cAMP/cGMP levels, worsening the motor deficits. Therefore, PDE10A inhibition may restore cyclic nucleotide signalling, rebalance basal ganglia pathways, and improve motor function, making it a promising therapeutic target for PD. Triazolopyridines are reported as potent PDE10A inhibitors and in the current research work this scaffold is selected for the in silico studies to build 3D QSAR model. Subsequently, after conducting pharmacophore modelling, the AAHHHR₁ model with two hydrogen bond acceptors (A1, A2), three hydrophobic interactions (H5, H6, H9), and one aromatic ring (R13) was selected to screen the NPASS database. 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. MD studies confirmed the stability of hits with PDE10A, forming favourable hydrogen bond interactions throughout a trajectory of 200 ns. Lastly, MM/PBSA showed that out of the five hits, complex NPASS₆815 showed better binding free energy of -30. 26 kcal/mol when compared to the reference molecules (-23. 38 kcal/mol). Thus, it was concluded that this molecule can act as potent PDE10A inhibitors and could serve as lead compounds for the development of new therapeutic agents for the Parkinson’s disease.

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