title: Computer-based design of novel HIV-1 entry inhibitors: neomycin conjugated to arginine peptides at two specific sites.
abstract: Aminoglycoside-arginine conjugates (AAC and APAC) are multi-target inhibitors of human immunodeficiency virus type-1 (HIV-1). Here, we predict new conjugates of neomycin with two arginine peptide chains binding at specific sites on neomycin [poly-arginine-neomycin-poly-arginine (PA-Neo-PA)]. The rationale for the design of such compounds is to separate two short arginine peptides with neomycin, which may extend the binding region of the CXC chemokine receptor type 4 (CXCR4). We used homology models of CXCR4 and unliganded envelope glycoprotein 120 (HIV-1(IIIB) gp120) and docked PA-Neo-PAs and APACs to these using a multistep docking procedure. The results indicate that PA-Neo-PAs spread over two negatively charged patches of CXCR4. PA-Neo-PA-CXCR4 complexes are energetically more favorable than AACs/APAC-CXCR4 complexes. Notably, our CXCR4 model and docking procedure can be applied to predict new compounds that are either inhibitors of gp120-CXCR4 binding without affecting stromal cell-derived factor 1 alpha (SDF-1 alpha) chemotaxis activity, or inhibitors of SDF-1 alpha-CXCR4 binding resulting in an anti-metastasis effect. We also predict that PA-Neo-PAs and APACs can interfere with CD4-gp120 binding in unliganded conformation.
authors.affiliation: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Berchanski
authors.forename: Aviva
authors.initials: A
authors.lastname: Lapidot
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009355:Neomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
chemical_list: D000617:Aminoglycosides; D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D011500:Protein Synthesis Inhibitors; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1; D001120:Arginine; D009355:Neomycin