Russian version English version
Volume 8   Issue 1   Year 2013
Andrianov A.M., Kornoushenko Yu.V., Kashyn I.A., Tuzikov A.V.

Computer-Aided Design of Novel HIV-1 Entry Inhibitors Based on Glycosphingolipids

Mathematical Biology & Bioinformatics. 2013;8(1):258-275.

doi: 10.17537/2013.8.258.


  1. Hartley O, Klasse PJ, Sattentau QJ, Moore JP. V3: HIV′s Switch-Hitter. AIDS Res. Hum. Retroviruses. 2005;21:171-189. doi: 10.1089/aid.2005.21.171
  2. Sirois S, Sing T, Chou KC. HIV-1 gp120 V3 loop for structure-based drug design. Curr. Protein Pept. Sci. 2005;6:413-422. doi: 10.2174/138920305774329359
  3. Andrianov AM. Human immunodeficiency virus-1 gp120 V3 loop for anti-acquired immune deficiency syndrome drug discovery: computer-aided approaches to the problem solving. Expert Opin. Drug. Discov. 2011;6:419-435. doi: 10.1517/17460441.2011.560603
  4. LaRosa GJ, Davide JP, Weinhold K, Waterbury JA, Profy AT, Lewis JA, Langlois AJ, Dressman GR, Boswell RN, Shadduk P, Holley LH, Karplus M, Bolognesi DP, Matthews TJ, Emini EA, Putney SD. Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant. Science. 1990;249:932-935. doi: 10.1126/science.2392685
  5. Tian H, Lan C, Chen YH. Sequence variation and consensus sequence of V3 loop on HIV-1 gp120. Immuno.l Lett. 2002;83:231-233. doi: 10.1016/S0165-2478(02)00101-3
  6. Andrianov AM, Anishchenko IV, Tuzikov AV. Discovery of novel promising targets for anti-AIDS drug developments by computer modeling: application to the HIV-1 gp120 V3 loop. J. Chem. Inf. Model. 2011;51:2760-2767. doi: 10.1021/ci200255t
  7. Andrianov AM, Kornoushenko YuV, Anishchenko IV, Eremin VF, Tuzikov AV. Structural analysis of the envelope gp120 V3 loop for some HIV-1 variants circulating in the countries of Eastern Europe. J. Biomol. Struct. Dynam. 2012:1-19. doi:10.1080/07391102.2012.706455. doi: 10.1080/07391102.2012.706455
  8. Jiang X, Burke V, Totrov M, Williams C, Cardozo T, Gorny MK, Zolla-Pazner S, Kong XP. Conserved structural elements in the V3 crown of HIV-1 gp120. Nat. Struct. Mol. Biol. 2010;17:955-961. doi: 10.1038/nsmb.1861
  9. Bhat S, Spitalnik SL, Gonzalez-Scarano F, Silberberg DH. Galactosylceramide or a derivative is an essential component of the neural receptor for human immunodeficiency virus type 1 envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA. 1991;88:7131-7134. doi: 10.1073/pnas.88.16.7131
  10. Fantini J, Cook DG, Nathanson N, Spitalnik SL, Gonzalez-Scarano F. Infection of colonic epithelial cell lines by type 1 human immunodeficiency virus is associated with cell surface expression of galactosylceramide, a potential alternative gp120 receptor. Proc. Natl. Acad. Sci. USA. 1993;90:2700-2704. doi: 10.1073/pnas.90.7.2700
  11. Fantini J, Hammache D, Delézay O, Yahi N, André-Barrès C, Rico-Lattes I, Lattes A. Synthetic soluble analogs of galactosylceramide (GalCer) bind to the V3 domain of HIV-1 gp120 and inhibit HIV-1-induced fusion and entry. J. Biol. Chem. 1997;272:7245-7252. doi: 10.1074/jbc.272.11.7245
  12. Yahi N, Sabatier JM, Nickel P, Mabrouk K, Gonzalez-Scarano F, Fantini J. Suramin inhibits binding of the V3 region of HIV-1 envelope glycoprotein gp120 to galactosylceramide, the receptor for HIV-1 gp120 on human colon epithelial cells. J. Biol. Chem. 1994;269:24349-24353.
  13. Cook DG, Fantini J, Spitalnik SL, Gonzalez-Scarano F. Binding of human immunodeficiency virus type I (HIV-1) gp120 to galactosylceramide (GalCer): relationship to the V3 loop. Virology. 1994;201:206-214. doi: 10.1006/viro.1994.1287
  14. Garg H, Francella N, Tony KA, Augustine LA, Barchi JJ Jr, Fantini J, Puri A, Mootoo DR, Blumenthal R. Glycoside analogs of beta-galactosylceramide, a novel class of small molecule antiviral agents that inhibit HIV-1 entry. Antiviral Res. 2008;80:54-61. doi: 10.1016/j.antiviral.2008.04.004
  15. LaBell RY, Jacobsen NE, Gervay-Hague J, O'Brien DF. Synthesis of novel glycolipids that bind HIV-1 Gp120. Bioconjug. Chem. 2002;13:143-149. doi: 10.1021/bc015533r
  16. Augustin LA, Fantini J, Mootoo DR. C-Glycoside analogues of beta-galactosylceramide with a simple ceramide substitute: synthesis and binding to HIV-1 gp120. Bioorg. Med. Chem. 2006;14:1182-1188. doi: 10.1016/j.bmc.2005.09.044
  17. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The Protein Data Bank. Nucl. Acids Res. 2000;28:235-242. doi: 10.1093/nar/28.1.235
  18. Andrianov AM, Anishchenko IV, Kisel MA, Kornoushenko YuV, Nikolayevich VA, Eremin VF, Kucherov II, Tuzikov AV. Computer-Aided Design of Novel HIV-1 Entry Inhibitors Targeting the Envelope gp120 V3 Loop. Biopolym. Cell. 2012;28:468-476. doi: 10.7124/bc.000139
  19. Curtiss LA, Raghavachari K, Redfern PC, Pople JA. Assessment of Gaussian-3 and density functional theories for a larger experimental test set. J. Chem. Phys. 2000;112:7374-7383. doi: 10.1063/1.481336
  20. Curtiss LA, Raghavachari K. Gaussian-3 and related methods for accurate thermochemistry. Theor. Chem. Acc. 2002;108:61-70. doi: 10.1007/s00214-002-0355-9
  21. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. Development and testing of a general Amber force field. J. Comput. Chem. 2004;25:1157-1174. doi: 10.1002/jcc.20035
  22. Ben-Israel A. A modified Newton-Rafson method for the solution of systems of equations. Israel J. Math. 1965;3:94-98. doi: 10.1007/BF02760034
  23. Bayly CI, Cieplak P, Cornell W, Kollman PA. Well-behaved electrostatic potential based method using charge restraints for determining atom-centered charges: the RESP model. J. Phys. Chem. 1993;97:10269-10280. doi: 10.1021/j100142a004
  24. Cornell WD, Cieplak P, Bayly CI, Kollmann PA. Application of the RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation. J. Am. Chem. Soc. 1993;115:9620-9631. doi: 10.1021/ja00074a030
  25. Andrianov AM, Kornoushenko YuV, Anishchenko IV, Eremin VF, Tuzikov AV. Structural analysis of the envelope gp120 V3 loop for some HIV-1 variants circulating in the countries of Eastern Europe. J. Biomol. Struct. Dynam. 2012:1-19.
  26. Huang CC, Tang M, Zhang MY, Majeed S, Montabana E, Stanfield RL, Dimitrov DS, Korber B, Sodroski J, Wilson IA, Wyatt R, Kwong PD. Structure of a V3-containing HIV-1 gp120 core. Science. 2005;310:1025-1028. doi: 10.1126/science.1118398
  27. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 2010;31:455-461.
  28. Kirkpatrick KS, Gelatt CD, Vecchi MP. Optimization by simulated annealing. Science. 1983;220:671-680. doi: 10.1126/science.220.4598.671
  29. Case DA, Darden TA, Cheatham TE, Simmerling CL, Wang J, Duke RE, Luo R, Crowley M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA. AMBER 11. San Francisco: University of California; 2010.
  30. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983;79:926-935. doi: 10.1063/1.445869
  31. Massova I, Kollman PA. Computational alanine scanning to probe protein-protein interactions: a novel approach to evaluate binding free energies. J. Am. Chem. Soc. 1999;121:8133-8143. doi: 10.1021/ja990935j
  32. Ablameiko SV, Abramov SM, Anishchenko VV, Medvedev SV, Paramonov NN, Chizh OP. Superkomp'iuternye konfiguratsii SKIF (SKIF supercomputer configuration). Minsk; 2005 (in Russ.).
  33. Durranta JD, McCammon JA. BINANA: A novel algorithm for ligand-binding characterization. J. Mol. Graph. Model. 2011;29:888-893. doi: 10.1016/j.jmgm.2011.01.004
  34. Anishchenko IV, Kashin IA, Tuzikov AV, Andrianov AM. Analysis of the energy of specific interactions between glycolipids, potential anti-HIV agents, and the V3 loopof the virus envelope gp120 protein. Doklady of the National Academy of Sciences of Belarus. 2012;56(4).
  35. Fantini J, Yahi N. Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Expert Rev. Mol. Med. 2010;12(e27):1-22. doi: 10.1017/S1462399410001602
  36. Mahfoud R, Garmy N, Maresca M, Yahi N, Puigserver A, Fantini J. Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins. J. Biol. Chem. 2002;277:11292-11296. doi: 10.1074/jbc.M111679200
  37. Yahi N, Aulas A, Fantini J. How Cholesterol Constrains Glycolipid Conformation for Optimal Recognition of Alzheimer's β Amyloid Peptide (Abeta1-40). PLoS One. 2010;5(2). Article No e9079. doi: 10.1371/journal.pone.0009079
  38. de Parseval A, Bobardt MD, Chatterji A, Chatterji U, Elder JH, David G, Zolla-Pazner S, Farzan M, Lee TH, Gallay PA. A highly conserved arginine in gp120 governs HIV-1 binding to both syndecans and CCR5 via sulfated motifs. J. Biol. Chem. 2005;280:39493-39504. doi: 10.1074/jbc.M504233200
  39. Wang WK, Dudek T, Zhao YJ, Brumblay HG, Essex M, Lee TH. CCR5 coreceptor utilization involves a highly conserved arginine residue of HIV type 1 gp120. Proc. Natl. Acad. Sci. USA. 1998;95:5740-5745. doi: 10.1073/pnas.95.10.5740
  40. Ogert RA, Lee MK, Ross W, Buckler-White A, Martin MA, Cho MW. N-linked glycosylation sites adjacent to and within the V1/V2 and the V3 loops of dualtropic human immunodeficiency virus type 1 isolate DH12 gp120 affect coreceptor usage and cellular tropism. J. Virol. 2001;75:5998-6006. doi: 10.1128/JVI.75.13.5998-6006.2001
  41. McCaffrey RA, Saunders C, Hensel M, Stamatatos L. N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J. Virol. 2004;78:3279-3295. doi: 10.1128/JVI.78.7.3279-3295.2004
  42. Teeraputon S, Louisirirojchanakul S, Auewarakul P. N-linked glycosylation in C2 region of HIV-1 envelope reduces sensitivity to neutralizing antibodies. Viral Immunol. 2005;18:343-353. doi: 10.1089/vim.2005.18.343
  43. Li Y, Rey-Cuille MA, Hu SL. N-linked glycosylation in the V3 region of HIV type 1 surface antigen modulates coreceptor usage in viral infection. AIDS Res. Hum. Retroviruses. 2001;17:1473-1479. doi: 10.1089/08892220152644179
  44. Malenbaum SE, Yang D, Cavacini L, Posner M, Robinson J, Cheng-Mayer C. The N-terminal V3 loop glycan modulates the interaction of clade A and B human immunodeficiency virus type 1 envelopes with CD4 and chemokine receptors. J. Virol. 2000;74:11008-11016. doi: 10.1128/JVI.74.23.11008-11016.2000
  45. Pollakis G, Kang S, Kliphuis A, Chalaby MI, Goudsmit J, Paxton WA. N-linked glycosylation of the HIV type-1 gp120 envelope glycoprotein as a major determinant of CCR5 and CXCR4 coreceptor utilization. J. Biol. Chem. 2001;276:13433-13441. doi: 10.1074/jbc.M009779200
  46. Polzer S, Dittmar MT, Schmitz H, Meyer B, Muller H, Krausslich HG, Schreiber M. Loss of N-linked glycans in the V3-loop region of gp120 is correlated to an enhanced infectivity of HIV-1. Glycobiology. 2001;11:11-19. doi: 10.1093/glycob/11.1.11
  47. Basmaciogullari S, Babcock GJ, Van Ryk D, Wojtowicz W, Sodroski J. Identification of conserved and variable structures in the human immunodeficiency virus gp120 glycoprotein of importance for CXCR4 binding. J. Virol. 2002;76:10791-10800. doi: 10.1128/JVI.76.21.10791-10800.2002
  48. Cormier EG, Dragic T. The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor. J. Virol. 2002;76:8953-8957. doi: 10.1128/JVI.76.17.8953-8957.2002
  49. Cormier EG, Tran DN, Yukhayeva L, Olson WC, Dragic T. Mapping the determinants of the CCR5 amino-terminal sulfopeptide interaction with soluble human immunodeficiency virus type 1 gp120-CD4 complexes. J. Virol. 2001;75:5541-5549. doi: 10.1128/JVI.75.12.5541-5549.2001
  50. Hoffman TL, LaBranche CC, Zhang W, Canziani G, Robinson J, Chaiken I, Hoxie JA, Doms RW. Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1 envelope protein. Proc. Natl. Acad. Sci. U.S.A. 1999;96:6359-6364. doi: 10.1073/pnas.96.11.6359
  51. Huang CC, Lam SN, Acharya P, Tang M, Xiang SH, Hussan SS, Stanfield RL, Robinson J, Sodroski J, Wilson IA, Wyatt R, Bewley CA, Kwong PD. Structures of theCCR5Nterminus and of a tyrosine-sulfatedantibody with HIV-1 gp120 and CD4. Science. 2007;317:1930-1934. doi: 10.1126/science.1145373
  52. Hu Q, Trent JO, Tomaras GD, Wang Z, Murray JL, Conolly SM, Navenot JM, Barry AP, Greenberg ML, Peiper SC. Identification of Env determinants in V3 that influence the molecular anatomy of CCR5 utilization. J. Mol. Biol. 2000;302:359-375. doi: 10.1006/jmbi.2000.4076
  53. Shimizu N, Haraguchi Y, Takeuchi Y, Soda Y, Kanbe K, Hoshino H. Changes in and discrepancies between cell tropisms and coreceptor uses of human immunodeficiency virus type 1 induced by single point mutations at the V3 tip of the env protein. Virology. 1999;259:324-333. doi: 10.1006/viro.1999.9764
  54. Ivanoff LA, Looney DJ, McDanal C, Morris JF, Wong-Staal F, Langlois AJ, Petteway SR Jr, Matthews TJ. Alteration of HIV-1 infectivity and neutralization by a single amino acid replacement in the V3 loop domain. AIDS Res. Hum. Retroviruses. 1991;7:595-603. doi: 10.1089/aid.1991.7.595
  55. Takeuchi Y, Akutsu M, Murayama K, Shimizu N, Hoshino H. Host range mutant of human immunodeficiency virus type 1: modification of cell tropism by a single point mutation at the neutralization epitope in the env gene. J. Virol. 1991;65:710-1718.
  56. Ivanoff LA, Dubay JW, Morris JF, Roberts SJ, Gutshall L, Sternberg EJ, Hunter E, Matthews TJ, Petteway SR Jr. V3 loop region of the HIV-1 gp120 envelope protein is essential for virus infectivity. Virology. 1992;187:423-432. doi: 10.1016/0042-6822(92)90444-T
  57. Grimaila RJ, Fuller BA, Rennert PD, Nelson MB, Hammarskjöld ML, Potts B, Murray M, Putney SD, Gray G. Mutations in the principal neutralization determinant of human immunodeficiency virus type 1 affect syncytium formation, virus infectivity, growth kinetics, and neutralization. J. Virol. 1992;66:1875-1883.
  58. Nehete PN, Vela EM, Hossain MM, Sarkar AK, Yahi N, Fantini J, Sastry KJ. A post-CD4-binding step involving interaction of the V3 region of viral gp120 with host cell surface glycosphingolipids is common to entry and infection by diverse HIV-1 strains. Antiviral Res. 2002;56:233-251. doi: 10.1016/S0166-3542(02)00130-4
  59. Harouse JM, Bhat S, Spitalnik SI, Laughlin M, Stefano K, Silberberg DH, Gonzalez-Scarano F. Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. Science. 1991;253:320-323. doi: 10.1126/science.1857969
  60. Anishchenko IV, Tuzikov AV, Andrianov AM. Computer-aided design of the potential drugs for AIDS therapy: β-galactosylceramide and the HIV-1 gp120 V3 Loop. Mathematical Biology and Bioinformatics. 2011;6(2):161-172 (in Russ.). doi: 10.17537/2011.6.161
Table of Contents Original Article
Math. Biol. Bioinf.
doi: 10.17537/2013.8.258
published in Russian

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