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Rational Design of HIV-1 Entry Inhibitors

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In Silico Models for Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 993))

Abstract

This chapter reviews studies that have used in silico techniques to design or identify potential HIV-1 entry inhibitors targeting cellular receptors CD4, CCR5, and CXCR4 and envelope glycoproteins, gp120 and gp41 of HIV-1. Both structure- and ligand-based design techniques have been used in those studies by applying diverse modeling techniques such as quantitative structure–activity relationship analysis, conformational analysis, molecular dynamics, pharmacophore generation, docking, virtual screening (using docking software and also shape-based ROCS techniques), and fragment-based design.

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References

  1. Biscone MJ, Pierson TC, Doms RW (2002) Opportunities and challenges in targeting HIV entry. Curr Opin Pharmacol 2:529–533

    Article  PubMed  CAS  Google Scholar 

  2. Starr-Spires LD, Collman RG (2002) HIV-1 entry and entry inhibitors as therapeutic agents. Clin Lab Med 22:681–701

    Article  PubMed  Google Scholar 

  3. Hertje M, Zhou M, Dietrich U (2010) Inhibition of HIV-1 entry: multiple keys to close the door. ChemMedChem 5:1825–1835

    Article  PubMed  CAS  Google Scholar 

  4. Sodroski JG (1999) HIV-1 entry inhibitors in the side pocket. Cell 99:243–246

    Article  PubMed  CAS  Google Scholar 

  5. Caffrey M (2011) HIV envelope: challenges and opportunities for development of entry inhibitors. Trends Microbiol 19:191–197

    Article  PubMed  CAS  Google Scholar 

  6. Jiang S, Debnath AK (2000) Development of HIV entry inhibitors targeted to the coiled coil regions of gp41. Biochem Biophys Res Commun 269:641–646

    Article  PubMed  CAS  Google Scholar 

  7. Jiang S, Zhao Q, Debnath AK (2002) Peptide and non-peptide HIV fusion inhibitors. Curr Pharm Des 8:563–580

    Article  PubMed  CAS  Google Scholar 

  8. Vita C, Drakopoulou E, Vizzavona J et al (1999) Rational engineering of a miniprotein that reproduces the core of the CD4 site interacting with HIV-1 envelope glycoprotein. Proc Natl Acad Sci USA 96:13091–13096

    Article  PubMed  CAS  Google Scholar 

  9. Wyatt R, Kwong PD, Desjardins E et al (1998) The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393:705–711

    Article  PubMed  CAS  Google Scholar 

  10. Martin L, Stricher F, Misse D et al (2003) Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes. Nat Biotechnol 21:71–76

    Article  PubMed  CAS  Google Scholar 

  11. Li H, Guan Y, Szczepanska A et al (2007) Synthesis and anti-HIV activity of trivalent CD4-mimetic miniproteins. Bioorg Med Chem 15:4220–4228

    Article  PubMed  CAS  Google Scholar 

  12. Zhao Q, Ma L, Jiang S et al (2005) Identification of N-phenyl-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4. Virology 339:213–225

    Article  PubMed  CAS  Google Scholar 

  13. Madani N, Schon A, Princiotto AM et al (2008) Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120. Structure 16:1689–1701

    Article  PubMed  CAS  Google Scholar 

  14. Yoshimura K, Harada S, Shibata J et al (2010) Enhanced exposure of human immunodeficiency virus type 1 primary isolate neutralization epitopes through binding of CD4 mimetic compounds. J Virol 84:7558–7568

    Article  PubMed  CAS  Google Scholar 

  15. Lalonde JM, Elban MA, Courter JR et al (2011) Design, synthesis and biological evaluation of small molecule inhibitors of CD4-gp120 binding based on virtual screening. Bioorg Med Chem 19:91–101

    Article  PubMed  CAS  Google Scholar 

  16. Yamada Y, Ochiai C, Yoshimura K et al (2010) CD4 mimics targeting the mechanism of HIV entry. Bioorg Med Chem Lett 20:354–358 16a.Kwon YD, Finzi A, Wu X et al (2012) Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci USA 109:5663–5668

    Article  PubMed  CAS  Google Scholar 

  17. Jones G, Willett P, Glen RC (1995) Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 245:43–53

    Article  PubMed  CAS  Google Scholar 

  18. Verdonk ML, Cole JC, Hartshorn MJ et al (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623

    Article  PubMed  CAS  Google Scholar 

  19. Grant JA, Gallardo MA, Pickup BT (1996) A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape. J Comput Chem 17:1653–1666

    Article  CAS  Google Scholar 

  20. Friesner RA, Banks JL, Murphy RB et al (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749

    Article  PubMed  CAS  Google Scholar 

  21. Halgren TA, Murphy RB, Friesner RA et al (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759

    Article  PubMed  CAS  Google Scholar 

  22. Caporuscio F, Tafi A, Gonzalez E et al (2009) A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 to identify new inhibitors of gp120-CD4 protein-protein interactions. Bioorg Med Chem Lett 19:6087–6091

    Article  PubMed  CAS  Google Scholar 

  23. Cornell WD, Cieplak P, Bayly CI et al (1995) A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J Am Chem Soc 117:5179–5197

    Article  CAS  Google Scholar 

  24. Goodford PJ (1985) A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J Med Chem 28:849–857

    Article  PubMed  CAS  Google Scholar 

  25. Boyd MR, Gustafson KR, McMahon JB et al (1997) Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother 41:1521–1530

    PubMed  CAS  Google Scholar 

  26. Dey B, Lerner DL, Lusso P et al (2000) Multiple antiviral activities of cyanovirin-N: blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses. J Virol 74:4562–4569

    Article  PubMed  CAS  Google Scholar 

  27. Esser MT, Mori T, Mondor I et al (1999) Cyanovirin-N binds to gp120 to interfere with CD4-dependent human immunodeficiency virus type 1 virion binding, fusion, and ­infectivity but does not affect the CD4 binding site on gp120 or soluble CD4-induced ­conformational changes in gp120. J Virol 73:4360–4371

    PubMed  CAS  Google Scholar 

  28. Patsalo V, Raleigh DP, Green DF (2011) Rational and computational design of stabilized variants of cyanovirin-N that retain affinity and specificity for glycan ligands. Biochemistry 50:10698–10712

    Article  PubMed  CAS  Google Scholar 

  29. Neffe AT, Meyer B (2004) A peptidomimetic HIV-entry inhibitor directed against the CD4 binding site of the viral glycoprotein gp120. Angew Chem Int Ed Engl 43:2937–2940

    Article  PubMed  CAS  Google Scholar 

  30. Wulfken J (2000) Development of CD4 binding peptides as inhibitors of HIV infection. Ph.D. Thesis, University of Hamburg, Germany

    Google Scholar 

  31. Neffe AT, Bilang M, Gruneberg I, Meyer B (2007) Rational optimization of the binding affinity of CD4 targeting peptidomimetics with potential anti HIV activity. J Med Chem 50:3482–3488

    Article  PubMed  CAS  Google Scholar 

  32. Lee DY, Lin X, Paskaleva EE et al (2009) Palmitic acid is a novel CD4 fusion inhibitor that blocks HIV entry and infection. AIDS Res Hum Retroviruses 25:1231–1241

    Article  PubMed  CAS  Google Scholar 

  33. Lin X, Paskaleva EE, Chang W et al (2011) Inhibition of HIV-1 infection in ex vivo cervical tissue model of human vagina by palmitic acid: implications for a microbicide development. PLoS One 6:e24803

    Article  PubMed  CAS  Google Scholar 

  34. Morris GM, Goodsell DS, Halliday RS et al (1998) Automated docking using Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  35. Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89:263–273

    Article  PubMed  CAS  Google Scholar 

  36. Weissenhorn W, Dessen A, Harrison SC et al (1997) Atomic structure of the ectodomain from HIV-1 gp41. Nature 387:426–430

    Article  PubMed  CAS  Google Scholar 

  37. Lu M, Blacklow SC, Kim PS (1995) A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol 2:1075–1082

    Article  PubMed  CAS  Google Scholar 

  38. Debnath AK, Radigan L, Jiang S (1999) Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1. J Med Chem 42:3203–3209

    Article  PubMed  CAS  Google Scholar 

  39. Good AC, Ewing TJ, Gschwend DA, Kuntz ID (1995) New molecular shape descriptors: application in database screening. J Comput Aided Mol Des 9:1–12

    Article  PubMed  CAS  Google Scholar 

  40. Shoichet BK, Bodian DL, Kuntz ID (1992) Molecular docking using shape descriptors. J Comput Chem 13:380–397

    Article  CAS  Google Scholar 

  41. Jiang S, Lin K, Lu M (1998) A conformation-specific monoclonal antibody reacting with fusion-active gp41 from the HIV-1 envelope glycoprotein. J Virol 72:10213–10217

    PubMed  CAS  Google Scholar 

  42. Jiang S, Lu H, Liu S et al (2004) N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob Agents Chemother 48:4349–4359

    Article  PubMed  CAS  Google Scholar 

  43. Liu B, Joseph RW, Dorsey BD et al (2009) Structure-based design of substituted biphenyl ethylene ethers as ligands binding in the hydrophobic pocket of gp41 and blocking the helical bundle formation. Bioorg Med Chem Lett 19:5693–5697

    Article  PubMed  CAS  Google Scholar 

  44. Clark M, Meshkat S, Talbot GT et al (2009) Fragment-based computation of binding free energies by systematic sampling. J Chem Inf Model 49:1901–1913

    Article  PubMed  CAS  Google Scholar 

  45. Liu K, Lu H, Hou L et al (2008) Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41. J Med Chem 51:7843–7854

    Article  PubMed  CAS  Google Scholar 

  46. Wang Y, Lu H, Zhu Q et al (2010) Structure-based design, synthesis and biological evaluation of new N-carboxyphenylpyrrole derivatives as HIV fusion inhibitors targeting gp41. Bioorg Med Chem Lett 20:189–192

    Article  PubMed  Google Scholar 

  47. Welch BD, VanDemark AP, Heroux A et al (2007) Potent D-peptide inhibitors of HIV-1 entry. Proc Natl Acad Sci USA 104:16828–16833

    Article  PubMed  CAS  Google Scholar 

  48. Eckert DM, Malashkevich VN, Hong LH et al (1999) Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 99:103–115

    Article  PubMed  CAS  Google Scholar 

  49. Tan JJ, Zhang B, Cong XJ et al (2011) Computer-aided design, synthesis, and biological activity evaluation of potent fusion inhibitors targeting HIV-1 gp41. Med Chem 7:309–316

    Article  PubMed  CAS  Google Scholar 

  50. Cong XJ, Tan JJ, Liu M et al (2010) Computational study of binding mode of N-substituted pyrrole derivatives to HIV-1 gp41. Prog Biochem Biophys 37:904–915

    Article  CAS  Google Scholar 

  51. Wang CX, Cong XJ, Kong R et al (2010) Binding mode of HIV-1 gp41 with its inhibitor NB-2. J Beijing Univ Technol 36:1118–1123

    Google Scholar 

  52. Kellenberger E, Springael JY, Parmentier M et al (2007) Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening. J Med Chem 50:1294–1303

    Article  PubMed  CAS  Google Scholar 

  53. Jain AN (2003) Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J Med Chem 46:499–511

    Article  PubMed  CAS  Google Scholar 

  54. Farzan M, Choe H, Vaca L et al (1998) A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J Virol 72:1160–1164

    PubMed  CAS  Google Scholar 

  55. Farzan M, Vasilieva N, Schnitzler CE et al (2000) A tyrosine-sulfated peptide based on the N-terminus of CCR5 interacts with a CD4-enhanced epitope of the HIV-1 gp120 envelope glycoprotein and inhibits HIV-1 entry. J Biol Chem 275:33516–33521

    Article  PubMed  CAS  Google Scholar 

  56. Farzan M, Mirzabekov T, Kolchinsky P et al (1999) Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96:667–676

    Article  PubMed  CAS  Google Scholar 

  57. Huang CC, Lam SN, Acharya P et al (2007) Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317:1930–1934

    Article  PubMed  CAS  Google Scholar 

  58. Acharya P, Dogo-Isonagie C, Lalonde JM et al (2011) Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry. ACS Chem Biol 6:1069–1077

    Article  PubMed  CAS  Google Scholar 

  59. Nardese V, Longhi R, Polo S et al (2001) Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES. Nat Struct Biol 8:611–615

    Article  PubMed  CAS  Google Scholar 

  60. Vangelista L, Longhi R, Sironi F et al (2006) Critical role of the N-loop and beta1-strand hydrophobic clusters of RANTES-derived peptides in anti-HIV activity. Biochem Biophys Res Commun 351:664–668

    Article  PubMed  CAS  Google Scholar 

  61. Lusso P, Vangelista L, Cimbro R et al (2011) Molecular engineering of RANTES peptide mimetics with potent anti-HIV-1 activity. FASEB J 25:1230–1243

    Article  PubMed  CAS  Google Scholar 

  62. Perez-Nueno VI, Pettersson S, Ritchie DW et al (2009) Discovery of novel HIV entry inhibitors for the CXCR4 receptor by prospective virtual screening. J Chem Inf Model 49:810–823

    Article  PubMed  CAS  Google Scholar 

  63. McGann M (2011) FRED pose prediction and virtual screening accuracy. J Chem Inf Model 51:578–596

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA

    Asim K. Debnath

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  1. Asim K. Debnath
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Editors and Affiliations

  1. , Dept. of Microbiology & Immunology, Drexel University College of Medicine, Queen Lane 2900, Philadelphia, 19129, Pennsylvania, USA

    Sandhya Kortagere

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Debnath, A.K. (2013). Rational Design of HIV-1 Entry Inhibitors. In: Kortagere, S. (eds) In Silico Models for Drug Discovery. Methods in Molecular Biology, vol 993. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-342-8_13

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  • DOI: https://doi.org/10.1007/978-1-62703-342-8_13

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-341-1

  • Online ISBN: 978-1-62703-342-8

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