Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC9867151 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Zhao Zixuan Z Ma Yinghong Y Li Xiangyuan X Morris-Natschke Susan L SL Sun Zhaocui Z Sun Zhonghao Z Ma Guoxu G Dong Zhengqi Z Zhao Xiaohong X Yang Meihua M Xu Xudong X Lee Kuohsiung K Wu Haifeng H Chen Chinho C

International journal of molecular sciences 20230111 2

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 ...[more]

PMID: 36674943

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Project description:Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r2), correlation coefficient of leave-one-out cross-validation (q2), Fisher's test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q2 = 0.583, Predr2 = 0.751) and CoMSIA (q2 = 0.690, Predr2 = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.

Dataset Information

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

Publications

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

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