title: Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.
abstract: Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.
authors: Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China. yuan-w-09@nwsuaf.edu.cn.
authors: Yuan
authors: Y
authors: Wang
authors: Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China. audi.lg@163.com.
authors: Mingwei
authors: M
authors: Wu
authors: Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian 116023, China. yling@dicp.ac.cn.
authors: Chunzhi
authors: C
authors: Ai
authors: Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China. yh_wang@nwsuaf.edu.cn.
authors: Yonghua
authors: Y
authors: Wang
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D055672:Static Electricity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; C029899:imidazole
keywords: 3D-QSAR; CoMFA; CoMSIA; DISCOtech; TNF-α; imidazoles; inhibitor; pharmacophore