Insights into the binding mode of curcumin to MD-2: studies from molecular docking, molecular dynamics simulations and experimental assessments.
Curcumin, a natural product, has been shown to possess notable anti-inflammatory activities and numerous studies have been carried out on its clinical applications. Recently, several reports mentioned that myeloid differentiation protein 2 (MD-2) may be the direct target of curcumin in the inhibition of lipopolysaccharide (LPS) signaling. However, the exact interaction between curcumin and MD-2 is still incompletely understood. In the present study, computational and experimental methods were employed to explore the underlying structural mechanism of curcumin binding to the MD-2 protein. Molecular docking and molecular dynamics (MD) simulation studies showed that curcumin could be embedded into the hydrophobic pocket of MD-2 and form stable hydrogen bonding interactions with residues R90 and Y102 of MD-2. Moreover, experimental results of curcumin binding to the MD-2(R90A/Y102A) mutant further confirmed that residues ARG-90 and TYR-102 contribute to the recognition process of curcumin binding to the MD-2 protein. In conclusion, we have explored the binding mechanism of curcumin to MD-2; more importantly, this work could offer useful references for designing novel analogs of curcumin as potential anti-inflammatory agents targeting the MD-2 protein.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. ypcai@wmu.edu.cn wzmcliangguang@163.com.
Zhe
Z
Wang
Gaozhi
G
Chen
Linfeng
L
Chen
Xing
X
Liu
Weitao
W
Fu
Yali
Y
Zhang
Chenglong
C
Li
Guang
G
Liang
Yuepiao
Y
Cai
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D001665:Binding Sites; D002460:Cell Line; D003474:Curcumin / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051218:Lymphocyte Antigen 96 / Q000737:chemistry*; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; D003474:Curcumin