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Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.

Publication ,  Journal Article
Zhao, Z; Ma, Y; Li, X; Morris-Natschke, SL; Sun, Z; Sun, Z; Ma, G; Dong, Z; Zhao, X; Yang, M; Xu, X; Lee, K; Wu, H; Chen, C
Published in: Int J Mol Sci
January 11, 2023

HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15ꞵ,16ꞵ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3ꞵ,25-diol 3-O-3′,3′-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.

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Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

January 11, 2023

Volume

24

Issue

2

Location

Switzerland

Related Subject Headings

  • Virus Replication
  • Quantitative Structure-Activity Relationship
  • Molecular Dynamics Simulation
  • Molecular Docking Simulation
  • Chemical Physics
  • Capsid Proteins
  • Anti-HIV Agents
  • 3404 Medicinal and biomolecular chemistry
  • 3107 Microbiology
  • 3101 Biochemistry and cell biology
 

Citation

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Zhao, Z., Ma, Y., Li, X., Morris-Natschke, S. L., Sun, Z., Ma, G., … Chen, C. (2023). Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations. Int J Mol Sci, 24(2). https://doi.org/10.3390/ijms24021430
Zhao, Zixuan, Yinghong Ma, Xiangyuan Li, Susan L. Morris-Natschke, Zhaocui Sun, Zhonghao Sun, Guoxu Ma, et al. “Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.Int J Mol Sci 24, no. 2 (January 11, 2023). https://doi.org/10.3390/ijms24021430.
Zhao, Zixuan, et al. “Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations.Int J Mol Sci, vol. 24, no. 2, Jan. 2023. Pubmed, doi:10.3390/ijms24021430.
Zhao Z, Ma Y, Li X, Morris-Natschke SL, Sun Z, Ma G, Dong Z, Zhao X, Yang M, Xu X, Lee K, Wu H, Chen C. Anti-HIV Potential of Beesioside I Derivatives as Maturation Inhibitors: Synthesis, 3D-QSAR, Molecular Docking and Molecular Dynamics Simulations. Int J Mol Sci. 2023 Jan 11;24(2).

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

January 11, 2023

Volume

24

Issue

2

Location

Switzerland

Related Subject Headings

  • Virus Replication
  • Quantitative Structure-Activity Relationship
  • Molecular Dynamics Simulation
  • Molecular Docking Simulation
  • Chemical Physics
  • Capsid Proteins
  • Anti-HIV Agents
  • 3404 Medicinal and biomolecular chemistry
  • 3107 Microbiology
  • 3101 Biochemistry and cell biology