title: Studies of H4R antagonists using 3D-QSAR, molecular docking and molecular dynamics.
abstract: 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.
authors.affiliation: Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian 116012, Liaoning, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hui-Xiao
authors.initials: HX
authors.lastname: Zhang
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D003198:Computer Simulation; D006633:Histamine Antagonists / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
chemical_list: C418607:HRH4 protein, human; D006633:Histamine Antagonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4