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Indexed by:期刊论文

Date of Publication:2014-01-01

Journal:BIOSYSTEMS

Included Journals:SCIE、PubMed

Volume:115

Page Number:13-22

ISSN No.:0303-2647

Key Words:Pyrimidine derivatives; Human A(2A) adenosine receptor; Molecular docking; Molecular dynamics; Thermodynamic analysis; 3D-QSAR

Abstract:The interaction of 278 monocyclic and bicyclic pyrimidine derivatives with human A(2A) adenosine receptor (AR) was investigated by employing molecular dynamics, thermodynamic analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches. The binding analysis reveals that the pyrimidine derivatives are anchored in TM2, 3, 5, 6 and 7 of A(2A) AR by the aromatic stacking and hydrogen bonding interactions. The key residues involving Phe168, Glu169, and Asn253 stabilize the monocyclic and bicyclic cores of inhibitors. The thermodynamic analysis by molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) approach also confirms the reasonableness of the binding modes. In addition, the ligand-/receptor-based comparative molecular similarity indices analysis (CoMSIA) models of high statistical significance were generated and the resulting contour maps correlate well with the structural features of the antagonists essential for high A(2A) AR affinity. A minor/bulky group with negative charge at C2/C6 of pyrimidine ring respectively enhances the activity for all these pyrimidine derivatives. Particularly, the higher electron density of the ring in the bicyclic derivatives, the more potent the antagonists. The obatined results might be helpful in rational design of novel candidate of A(2A) adenosine receptor antagonist for treatment of Parkinson's disease. (C) 2013 Elsevier Ireland Ltd. All rights reserved.