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论文类型：期刊论文

发表时间：2015-05-01

发表刊物：MEDICINAL CHEMISTRY RESEARCH

收录刊物：SCIE、Scopus

卷号：24

期号：5

页面范围：2033-2042

ISSN号：1054-2523

关键字：Pyrimidine derivatives; HCV replication (replicase) inhibitors; Pharmacophore modeling; 3D-QSAR

摘要：Three-dimensional quantitative structure activity relationship has been carried out on a series of 211 pyrimidine derivatives as HCV replication (replicase) inhibitors to identify the chemical structural impacting the biological activities. The QSAR models based on 157 compounds screened as the training set and the rest as the test set were established by comparative molecular field analysis and molecular similarity indices analysis (CoMSIA) methods. The optimal CoMSIA model exhibits both satisfying internal and external prediction performance with q (2) = 0.501, , . In addition, the 3D contour map analysis and the pharmacophoric features identified from corresponding pharmacophore study point out the key structural features that affect the inhibition activity of the pyrimidine analogs that (1) bulky substituents at position 11 and 23 are unfavorable; (2) minor positive 16 charges and H-bond donor groups at this position are benefit while H-bond acceptor near this position are detrimental; (3) substituents near Ring B: minor H-bond donor, H-bond acceptor groups are favorable; (4) electro-negative charges at position 7 and 9 are favorable while H-bond donor at position 9 are unfavorable; (5) two H-bond donor sites (DS1, DS2), two H-bond donor atoms (DA1, DA2); two H-bond acceptor atoms (AA1, AA2), hydrophobic and aromatic, and aromatic centers account for the pharmacophore features of the model.