QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A3 receptor subtype

Human adenosine A3 receptor (A3 AR) binding affinity of pyrazolotriazolopyrimidine derivatives (n = 116) has been subjected to QSAR analyses using three-dimensional (shape, spatial, electronic, and molecular field) along with thermodynamic descriptors to explore the physicochemical requirements for the binding. QSAR models have been validated internally [using leave-one-out cross-validation method] and externally [using test set molecules] to ensure the predictive capacity of the models. The models suggest that shape of the substituent at N8 position of the pyrazole ring should be optimum. Furthermore, lipophilic substituents having electronegative atoms at NH2 group of C5 position of the pyrimidine ring with distributed negative charge over the surface may enhance the binding affinity. Again, the carbamoylation of the NH2 group at C5 position of pyrimidine ring is an essential factor for binding with A3 receptor. The QSAR models were used for the design and development of some novel thienopyrimidines which were predicted to have good affinity towards A3 AR.

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