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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 …