QSAR, docking and molecular dynamics study guided repurposing of 2,4 substituted pyrimidine derivatives as 5 HT2C receptor antagonists for Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and impaired neurotransmission. Targeting the serotonin 5-HT2C receptor represents a promising strategy to restore dopaminergic balance; however, detailed structure-based investigations remain limited. This study employed an integrated computational framework combining 2D-QSAR modeling, molecular docking, molecular dynamics (MD) simulations, and ADMET profiling to identify novel 2,4-substituted pyrimidine derivatives as potential antagonist. A statistically robust 2D-QSAR model developed using QSARINS demonstrated strong predictive ability (R2_train = 0.8102, Q2_LOO = 0.7065, MAE_train = 0.0216). Virtual screening of 45 compounds identified top candidates with high predicted activity. Molecular docking against the 5-HT2C receptor (PDB ID: 6BQH) revealed superior binding affinities for Molecule-7 and Molecule-32 (− 8.376 and − 8.372 kcal/mol) compared to agomelatine (− 7.055 kcal/mol). Interaction analysis showed that Molecule-7 forms a key hydrogen bond with SER219 (3.98 Å) via the pyrimidine nitrogen, along with π–π interactions with PHE328 and TRP324, and hydrophobic contacts involving ALA222, VAL215, and ILE131. Similarly, Molecule-32 exhibited hydrogen bonding with VAL215 and π–π interactions with PHE328 and TRP324, contributing to binding stabilization. MD simulations (100 ns) confirmed stable protein–ligand complexes, supported by RMSD, RMSF, radius of gyration, and SASA profiles. MM-GBSA analysis indicated strong binding affinity, with compound 6BQH_7 showing the lowest energy (− 53.59 kcal/mol). ADMET profiling suggested favourable pharmacokinetics. Overall, this study highlights pyrimidine derivatives as promising scaffolds for further optimization and experimental validation against PD.