Abstract
Computational assessment of the binding interactions of drugs is an important component of computer-aided drug design paradigms. In this perspective, a set of 30 1-(substituted phenyl)-3-(naphtha[1, 2-d] thiazol-2-yl) urea/thiourea derivatives showing antiparkinsonian activity were docked into inhibitor binding cavity of human adenosine A(2A) receptor (AA2AR) to understand their mode of binding interactions in silico. Lamarckian genetic algorithm methodology was employed for docking simulations using AutoDock 4.2 program. The results signify that the molecular docking approach is reliable and produces a good correlation coefficient (r(2) = 0.483) between docking score and antiparkinsonian activity (in terms of % reduction in catalepsy score). Potent antiparkinsonian agents carried methoxy group in the phenyl ring, exhibited both hydrophilic and lipophilic interactions with lower energy of binding at the AA(2A)R. These molecular docking analyses should, in our view, contribute for further development of selective AA(2A)R antagonists for the treatment of Parkinson's disease.
Highlights
Adenosine A2A receptors (AA2AR) are highly distributed in the central nervous system and are found in abundance in the basal ganglia, a region of the brain associated with motor function [1]
adenosine A2A receptor (AA2AR) antagonists were found to diminish the symptoms of Parkinson’s disease (PD) and to potentiate the effect of levodopa [5], so, it may be possible to reduce the dose of the dopaminergic drugs and the occurrence of side effects
Correlation between docking scores and antiparkinsonian activity: The results signify that the molecular docking approach is reliable and produces a good correlation coefficient (r2 = 0.483) between docking score and antiparkinsonian activity
Summary
Adenosine A2A receptors (AA2AR) are highly distributed in the central nervous system and are found in abundance in the basal ganglia, a region of the brain associated with motor function [1]. AA2AR antagonists may provide a novel therapy for the treatment of Parkinson’s disease (PD) with lower risk of dyskinesias They may exhibit neuroprotective effects [4]. Certain thiazoles with a urea moiety [14] have demonstrated AA2AR antagonistic activities for the development of a suitable approach to the treatment of PD that may be the starting point for the future drug design. We have discovered urea derivatives of naphtha [1, 2-d] thiazol-2-amine as novel anti-Parkinsonian agents that cause neuroprotection against haloperidol-induced oxidative stress in mice [10] These findings have motivated us to reveal their interactions with AA2ARs insilico by using AutoDock program and to attest anti-Parkinsonian activity associated with them
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