In Silico Molecular Docking Study on the κ-Opioid Receptor Antagonists BU09059 and BU09057
[1]
Dan-Qi Zhao, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[2]
Wen-Xia Ren, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[3]
Mei-Na Qiu, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[4]
Ru-Peng Ou, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[5]
Hua-Jun Luo, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[6]
Zhi Xie, Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Science, China Three Gorges University, Yichang, China.
[7]
Wei-Qiao Deng, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
As the selective к-opioid receptor (KOR) antagonists, BU09059 and BU09057 were designed from JDTic by soft-drug principles. Although there were small differences in their chemical structures, BU09059 (Ki=1.72 nM) showed significantly higher affinity than analogue BU09057 (Ki=158.6 nM). To explain the interaction modes of BU09059 and BU09057 with KOR, in silico molecular docking calculations were studied using induced-fit docking (IFD) and molecular mechanics/generalized Born surface area (MM/GBSA) calculation methods. The docking Gscore, IFD score and ΔGbind (binding free energy) of BU09059 (-8.76, -793.07 and -33.84 kcal/mol) are lower than those of BU09057 (-7.84, -790.51 and -14.56 kcal/mol), which is consistent with the experimental affinity results. From the calculation analysis, there was the significant difference in binding with the key residues Asp138 and Tyr139. The binding energies of BU09059 with Asp138 and Tyr139 are -1.63 and -6.18 kcal/mol, while those of BU09057 are 5.04 and -0.03 kcal/mol. These results could promote the rational design of novel KOR antagonists.
BU09059, BU09057, к Opioid Receptor, Induced-Fit Docking, Binding Free Energy
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