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 (<b>1</b>) produced (20<i>S</i>,24<i>S</i>)-15<i>ꞵ</i>,16<i>ꞵ</i>-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3<i>ꞵ</i>,25-diol 3-<i>O</i>-3',3'-dimethylsuccinate (<b>3</b>, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound <b>1</b> 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 <b>3b</b> showed significant activity against HIV-1_NL4-3 with an EC₅₀ value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (<i>r</i>² = 0.99, <i>q</i>² = 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 &lt;2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.