title: In silico design of novel broad anti-HIV-1 agents based on glycosphingolipid β-galactosylceramide, a high-affinity receptor for the envelope gp120 V3 loop.
abstract: Novel anti-Human immunodeficiency virus (HIV)-1 agents targeting the V3 loop of envelope protein gp120 were designed by computer modeling based on glycosphingolipid β-galactosylceramide (β-GalCer), which is an alternative receptor allowing HIV-1 entry into CD4-negative cells of neural and colonic origin. Models of these β-GalCer analogs bound to the V3 loops from five various HIV-1 variants were generated by molecular docking and their stability was estimated by molecular dynamics (MDs) and binding free energy simulations. Specific binding to the V3 loop was accomplished primarily by non-conventional XH…π interactions between CH/OH sugar groups of the glycolipids and the conserved V3 residues with π-conjugated side chains. The designed compounds were found to block the tip and/or the base of the V3 loop, which form invariant structural motifs that contain residues critical for cell tropism. With the MDs calculations, the docked models of the complexes of the β-GalCer analogs with V3 are energetically stable in all of the cases of interest and exhibit low values of free energy of their formation. Based on the data obtained, these compounds are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics.
authors.affiliation: a Institute of Bioorganic Chemistry , National Academy of Sciences of Belarus , Kuprevich Street 5/2, Minsk 220141 , Republic of Belarus.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Andrianov
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kornoushenko
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Kashyn
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kisel
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Tuzikov
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D006028:Glycosphingolipids / Q000737:chemistry* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009005:Monosaccharides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015728:Receptors, HIV / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D002518:Ceramides; D006028:Glycosphingolipids; D015699:HIV Envelope Protein gp120; D009005:Monosaccharides; D015728:Receptors, HIV; C511581:beta-galactosyl ceramide
keywords: HIV-1; anti-HIV-1 agents; computer-aided drug design; glycolipid β-galactosylceramide; gp120 V3 loop