Chem. J. Chinese Universities ›› 2021, Vol. 42 ›› Issue (3): 758.doi: 10.7503/cjcu20200752

• Physical Chemistry • Previous Articles     Next Articles

Theoretical Study on the Unbinding Pathway of Xanthine Oxidase Inhibitors Based on Steered Molecular Dynamics Simulation

QI Renrui1, LI Minghao1, CHANG Hao2, FU Xueqi1, GAO Bo1, HAN Weiwei1, HAN Lu1, LI Wannan1()   

  1. 1.Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education,School of Life Science,Jilin University,Changchun 130012,China
    2.Jilin Province Teyi Food Biotechnology Company Limited,Changchun 130052,China
  • Received:2020-10-16 Online:2021-03-10 Published:2021-01-14
  • Contact: LI Wannan E-mail:liwannan@jlu.edu.cn
  • Supported by:
    ? Supported by the Science and Technology Development Project of Jilin Province, China(20200801069GH)

Abstract:

At present, Xanthine Oxidase(XO) inhibitors are the main drugs used to treat gout and hyperuricemia. The interaction between XO and inhibitors is a hot study spot. The unbinding pathway of XO inhibitors(Allopurinol and Puerarin) were analysed via steered molecular dynamics simulation. Molecular docking results showed that allopurinol and puerarin were bound to the MO-pt center of XO. Alanine scanning results indicted that Val789, Arg880, Phe911, Phe914 and Val1081 played very important roles for inhibitors binding to XO. The tunnel analysis based on CAVER 3.0 illustrated the shape of the tunnel was relatively regular, which was beneficial to the dissociation of the inhibitors. The steered molecular dynamics simulation results revealed that compared to puerarin, allopurinol needed more external force and longer time to escape from XO. In addition, Phe1009, Arg880, Ala1079, Val1011 and Thr1010 all played important roles in maintaining the structural stability of the two compounds binding to XO, Phe649 and Phe1013 functioned a gating role in the process of inhibitor dissociation, and His875 played a blocking role in inhibitors dissociation. The results provided some theoretical clues for the study of the interaction between inhibitors and XO. Puerarin can be developed as a mild candidate medicine for the treatment of gout in the future.

Key words: Xanthine oxidase, Allopurinol, Puerarin, Gout, Steered molecular dynamics simulation

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