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Three-dimensional quantitative structure–activity relationship (3D-QSAR) modelling was conducted on a series of leucine-rich repeat kinase 2 (LRRK2) antagonists using CoMFA and CoMSIA methods. The data set, which consisted of 37 molecules, was divided into training and test subsets by using a hierarchical clustering method. Both CoMFA and CoMSIA models were derived using a training set on the basis of the common substructure-based alignment. The optimum PLS model built by CoMFA and CoMSIA provided satisfactory statistical results (q2= 0.589 andr2= 0.927 andq2= 0.473 andr2= 0.802, respectively). The external predictive ability of the models was evaluated by using seven compounds. Moreover, an external evaluation set with known experimental data was used to evaluate the external predictive ability of the porposed models. The statistical parameters indicated that CoMFA (after region focusing) has high predictive ability in comparison with standard CoMFA and CoMSIA models. Molecular docking was also performed on the most active compound to investigate the existence of interactions between the most active inhibitor and the LRRK2 receptor. Based on the obtained results and CoMFA contour maps, some features were introduced to provide useful insights for designing novel and potent LRRK2 inhibitors. [ABSTRACT FROM AUTHOR]

Parkinson’s disease affects millions of people around the world. Recently, adenosine A2Areceptor antagonists have been identified as a drug target for the treatment of Parkinson’s disease. Consequently, there is an immediate need to develop new classes of A2Areceptor antagonists. In the present analysis, three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed on a series of pyrimidines, using comparative molecular field analysis (CoMFA). The best prediction was obtained with a CoMFA standard model (q2= 0.475,r2= 0.977) and a CoMFA region focusing model (q2= 0.637,r2= 0.976) combined with steric and electrostatic fields. The structural insights derived from the contour maps helped to better interpret the structure–activity relationships. Also, to understand the structure–activity correlation of A2Areceptor antagonists, we have carried out molecular docking analysis. Based on the results obtained from the present 3D-QSAR and docking studies, we have identified some key features for increasing the activity of compounds, which have been used to design new A2Areceptor antagonists. The newly designed molecules showed high activity with the obtained models. [ABSTRACT FROM PUBLISHER]