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论文类型：期刊论文

发表时间：2012-03-01

发表刊物：JOURNAL OF MOLECULAR MODELING

收录刊物：SCIE、PubMed、Scopus

卷号：18

期号：3

页面范围：991-1001

ISSN号：1610-2940

关键字：3D-QSAR; H4R antagonist; CoMFA; CoMSIA; MD; Docking

摘要：Three-dimensional quantitative structure-activity relationship studies were performed on a series of 88 histamine receptor 4 (H4R) antagonists in an attempt to elucidate the 3D structural features required for activity. Several in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), molecular docking, and molecular dynamics (MD), were carried out. The results show that both the ligand-based CoMFA model (Q(2)=0.548, R-ncv(2)=0.870, R-pre(2)=0.879, SEE=0.410, SEP=0.386) and the CoMSIA model (Q(2)=0.526, R-ncv(2)=0.866, R-pre(2)=0.848, SEE=0.416, SEP=0.413) are acceptable, as they show good predictive capabilities. Furthermore, a combined analysis incorporating CoMFA, CoMSIA contour maps and MD results shows that (1) compounds with bulky or hydrophobic substituents at positions 4-6 in ring A (R2 substituent), positively charged or hydrogen-bonding (HB) donor groups in the R1 substituent, and hydrophilic or HB acceptor groups in ring C show enhanced biological activities, and (2) the key amino acids in the binding pocket are TRP67, LEU71, ASP94, TYR95, PHE263 and GLN266. To our best knowledge, this work is the first to report the 3D-QSAR modeling of these H4R antagonists. The conclusions of this work may lead to a better understanding of the mechanism of antagonism and aid in the design of new, more potent H4R antagonists.