Therapeutic exploration potential of adenosine receptor antagonists through pharmacophore ligand-based modelling and pharmacokinetics studies against Parkinson disease.

Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects persons aged 65 and older. It leads to a decline in motor function as a result of the buildup of abnormal protein deposits called Lewy bodies in the brain. Existing therapies exhibit restricted effectiveness and undesirable side effects. The objective was to discover potent medications that have demonstrated effectiveness in treating PD by employing computational methods. This work employed a comprehensive approach to evaluate 70 pyrimidine derivatives for their potential in treating PD. The evaluation involved the use of QSAR modelling, virtual screening, molecular docking, MD simulation, ADMET analysis, and antagonist inhibitor creation. Six compounds passed all the evaluation, while for MD simulation, carried out between the compound with best docking score and the reference drug, compound 57 was discovered to possess more stability compared to theophylline which is the reference drug, and it functions as a primary inhibitor of the adenosine A_2A receptor. Additionally, the study determined that compound 57 satisfied the Rule of Five (Ro5) standards and exhibited robust physicochemical characteristics. The compound exhibited moderate to low levels of hERG inhibition. The conducted investigations highlighted promising outcomes of natural compounds that can orient towards the rational development of effective Parkinson's disease inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00305-9.