title: Insight into the binding mode and the structural features of the pyrimidine derivatives as human A2A adenosine receptor antagonists.
abstract: The interaction of 278 monocyclic and bicyclic pyrimidine derivatives with human A2A 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 A2A 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 A2A 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 A2A adenosine receptor antagonist for treatment of Parkinson's disease.
authors.affiliation: Bioinformatics Center, Northwest A & F University, Yangling, Shaanxi 712100, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Zhang
authors.affiliation: College of Economics and Management, Northwest A & F University, Yangling, Shaanxi 712100, China. Electronic address: Ltj168168@126.com.
authors.forename: Tianjun
authors.initials: T
authors.lastname: Liu
authors.affiliation: Bioinformatics Center, Northwest A & F University, Yangling, Shaanxi 712100, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Bioinformatics Center, Northwest A & F University, Yangling, Shaanxi 712100, China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Modeling and Design, Chinese Academy of Sciences, Dalian, Liaoning 116024, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116012, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, The Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Bioinformatics Center, Northwest A & F University, Yangling, Shaanxi 712100, China. Electronic address: yh_wang@nwsuaf.edu.cn.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010300:Parkinson Disease / Q000188:drug therapy; D011485:Protein Binding; D011743:Pyrimidines / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines
keywords: 3D-QSAR; Human A(2A) adenosine receptor; Molecular docking; Molecular dynamics; Pyrimidine derivatives; Thermodynamic analysis