title: 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 A(3) receptor subtype.
abstract: Human adenosine A(3) receptor (A(3) 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 N(8) position of the pyrazole ring should be optimum. Furthermore, lipophilic substituents having electronegative atoms at NH(2) group of C(5) position of the pyrimidine ring with distributed negative charge over the surface may enhance the binding affinity. Again, the carbamoylation of the NH(2) group at C(5) position of pyrimidine ring is an essential factor for binding with A(3) receptor. The QSAR models were used for the design and development of some novel thienopyrimidines which were predicted to have good affinity towards A(3) AR.
authors.affiliation: Pharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and UGC Center of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University, Chandigarh 160 014, India.
authors.forename: D
authors.initials: D
authors.lastname: Pran Kishore
authors.forename: C
authors.initials: C
authors.lastname: Balakumar
authors.forename: A
authors.initials: A
authors.lastname: Raghuram Rao
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Roy
authors.forename: Kunal
authors.initials: K
authors.lastname: Roy
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; C477655:Pyrazolotriazolopyrimidine; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles