title: Determination of the binding mode for anti-inflammatory natural product xanthohumol with myeloid differentiation protein 2.
abstract: It is recognized that myeloid differentiation protein 2 (MD-2), a coreceptor of toll-like receptor 4 (TLR4) for innate immunity, plays an essential role in activation of the lipopolysaccharide signaling pathway. MD-2 is known as a neoteric and suitable therapeutical target. Therefore, there is great interest in the development of a potent MD-2 inhibitor for anti-inflammatory therapeutics. Several studies have reported that xanthohumol (XN), an anti-inflammatory natural product from hops and beer, can block the TLR4 signaling by binding to MD-2 directly. However, the interaction between MD-2 and XN remains unknown. Herein, our work aims at characterizing interactions between MD-2 and XN. Using a combination of experimental and theoretical modeling analysis, we found that XN can embed into the hydrophobic pocket of MD-2 and form two stable hydrogen bonds with residues ARG-90 and TYR-102 of MD-2. Moreover, we confirmed that ARG-90 and TYR-102 were two necessary residues during the recognition process of XN binding to MD-2. Results from this study identified the atomic interactions between the MD-2 and XN, which will contribute to future structural design of novel MD-2-targeting molecules for the treatment of inflammatory diseases.
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Weitao
authors: W
authors: Fu
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Lingfeng
authors: L
authors: Chen
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Zhe
authors: Z
authors: Wang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Chengwei
authors: C
authors: Zhao
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Gaozhi
authors: G
authors: Chen
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Xing
authors: X
authors: Liu
authors: Department of Respiratory Medicine, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors: Yuanrong
authors: Y
authors: Dai
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Yuepiao
authors: Y
authors: Cai
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA.
authors: Chenglong
authors: C
authors: Li
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Jianmin
authors: J
authors: Zhou
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou, Zhejiang, People's Republic of China.
authors: Guang
authors: G
authors: Liang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D002460:Cell Line; D005419:Flavonoids / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008962:Models, Theoretical; D011427:Propiophenones / Q000378:metabolism*; D011485:Protein Binding; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D011427:Propiophenones; D051197:Toll-Like Receptor 4; C104536:xanthohumol
keywords: binding mode; inflammation; molecular dynamics simulation; myeloid differentiation 2; xanthohumol