Identification of old drugs as potential inhibitors of HIV-1 integrase -human LEDGF/p75 interaction via molecular docking

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• 作者：Guoping Hu (1)
  Xi Li (1)
  Xianqiang Sun (1)
  Weiqiang Lu (1)
  Guixia Liu (1)
  Jin Huang (1)
  Xu Shen (2)
  Yun Tang (1)
  
• 关键词：Drug repositioning ; HIV ; 1 Integrase ; Human LEDGF/p75 protein ; Molecular docking ; Protein ; protein interaction
• 刊名：Journal of Molecular Modeling
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：18
• 期：12
• 页码：4995-5003
• 全文大小：549KB
• 参考文献：1. Anthony NJ (2004) HIV-1 integrase: a target for new AIDS chemotherapeutics. Curr Top Med Chem 4:979-90 CrossRef
  2. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF, Katlama C, Calvez V, Marcelin AG (2008) Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother 52:1351-358. doi:10.1128/Aac.01228-07 CrossRef
  3. Van Maele B, Busschots K, Vandekerckhove L, Christ F, Debyser Z (2006) Cellular co-factors of HIV-1 integration. Trends Biochem Sci 31:98-05. doi:10.1016/j.tibs.2005.12.002 CrossRef
  4. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo WL, Poeschla EM (2006) An essential role for LEDGF/p75 in HIV integration. Science 314:461-64. doi:10.1126/science.1132319 CrossRef
  5. Vanegas M, Llano M, Delgado S, Thompson D, Peretz M, Poeschla E (2005) Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering. J Cell Sci 118:1733-743. doi:10.1242/jcs.02299 CrossRef
  6. Al-Mawsawi LQ, Neamati N (2007) Blocking interactions between HIV-1 integrase and cellular cofactors: an emerging anti-retroviral strategy. Trends Pharmacol Sci 28:526-35. doi:10.1016/j.tips.2007.09.005 CrossRef
  7. Poeschla EM (2008) Integrase, LEDGF/p75 and HIV replication. Cell Mol Life Sci 65:1403-424. doi:10.1007/s00018-008-7540-5 CrossRef
  8. De Rijck J, Vandekerckhove L, Gijsbers R, Hombrouck A, Hendrix J, Vercammen J, Engelborghs Y, Christ F, Debyser Z (2006) Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J Virol 80:11498-1509. doi:10.1128/Jvi.00801-06 CrossRef
  9. Cherepanov P, Ambrosio ALB, Rahman S, Ellenberger T, Engelman A (2005) Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci USA 102:17308-7313. doi:10.1073/pnas.0506921402 CrossRef
  10. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nat Rev Drug Discovery 3:301-17. doi:10.1038/Nrd1343 CrossRef
  11. Du L, Zhao YX, Chen J, Yang LM, Zheng YT, Tang Y, Shen X, Jiang HL (2008) D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75. Biochem Biophys Res Commun 375:139-44. doi:10.1016/j.bbrc.2008.07.139 CrossRef
  12. De Luca L, Barreca ML, Ferro S, Christ F, Iraci N, Gitto R, Monforte AM, Debyser Z, Chimirri A (2009) Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. Chem Med Chem 4:1311-316. doi:10.1002/cmdc.200900070
  13. Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, Van der Veken NJ, Van Remoortel B, Strelkov SV, De Maeyer M, Chaltin P, Debyser Z (2010) Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 6:442-48. doi:10.1038/Nchembio.370 CrossRef
  14. De Luca L, Ferro S, Gitto R, Barreca ML, Agnello S, Christ F, Debyser Z, Chimirri A (2010) Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg Med Chem 18:7515-521. doi:10.1016/j.bmc.2010.08.051 CrossRef
  15. De Luca L, Ferro S, Morreale F, De Grazia S, Chimirri A (2011) Inhibitors of the Interactions between HIV-1 IN and the Cofactor LEDGF/p75. Chem Med Chem 6:1184-191. doi:10.1002/cmdc.201100071
  16. Prime, version 2.1, Schr?dinger, LLC, New York, NY, 2009
  17. MacroModel, version 9.7, Schr?dinger, LLC, New York, NY, 2009
  18. Accelrys Software Inc., Discovery Studio Modeling Environment, Release 2.5, Accelrys, Inc, San Diego, CA, USA, 2004, http://accelrys.com/
  19. Fang J, Shen J, Cheng FX, Xu ZJ, Liu GX, Tang Y (2011) Computational insights into ligand selectivity of estrogen receptors from pharmacophore modeling. Mol Inform 30:539-49. doi:10.1002/minf.201000170 CrossRef
  20. Kuang GL, Hu GP, Sun XQ, Li WH, Liu GX, Tang Y (2012) In silico investigation of interactions between human cannabinoid receptor-1 and its antagonists. J Mol Model. doi:10.1007/s00894-012-1381-8
  21. Hu GP, Kuang GL, Xiao W, Li WH, Liu GX, Tang Y (2012) Performance evaluation of 2D fingerprint and 3D shape similarity methods in virtual screening. J Chem Inf Model. doi:10.1021/ci300030u
  22. Jahn A, Hinselmann G, Fechner N, Zell A (2009) Optimal assignment methods for ligand-based virtual screening. J Chem Inf 1:14. doi:10.1186/1758-2946-1-14
  23. Jain AN, Nicholls A (2008) Recommendations for evaluation of computational methods. J Comput Aided Mol Des 22:133-39. doi:10.1007/s10822-008-9196-5 CrossRef
  24. LigPrep, version 2.3, Schr?dinger, LLC, New York, NY, 2009
  25. Glide, version 5.5, Schr?dinger, LLC, New York, NY, 2009
  26. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739-749. doi:10.1021/jm0306430 CrossRef
  27. Brooijmans N, Humblet C (2010) Chemical space sampling by different scoring functions and crystal structures. J Comput Aided Mol Des 24:433-47. doi:10.1007/s10822-010-9356-2 CrossRef
  28. Jenkins TM, Engelman A, Ghirlando R, Craigie R (1996) A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxyl-terminal domains in multimerization. J Biol Chem 271:7712-718 CrossRef
  29. Hou Y, McGuinness DE, Prongay AJ, Feld B, Ingravallo P, Ogert RA, Lunn CA, Howe JA (2008) Screening for antiviral inhibitors of the HIV integrase - LEDGF/p75 interaction using the AlphaScreen (TM) luminescent proximity assay. J Biomol Screening 13:406-14. doi:10.1177/1087057108317060 CrossRef
  30. Zhao Y, Li W, Zeng J, Liu G, Tang Y (2008) Insights into the interactions between HIV-1 integrase and human LEDGF/p75 by molecular dynamics simulation and free energy calculation. Proteins 72:635-45. doi:10.1002/prot.21955 CrossRef
  31. Busschots K, Voet A, De Maeyer M, Rain JC, Emiliani S, Benarous R, Desender L, Debyser Z, Christ F (2007) Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol 365:1480-492. doi:10.1016/j.jmb.2006.10.094 CrossRef
  32. Penzak SR, Chuck SK (2000) Hyperlipidemia associated with HIV protease inhibitor use: pathophysiology, prevalence, risk factors and treatment. Scand J Infect Dis 32:111-23 CrossRef
  33. Del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, Alegret M, Pena JM, Rodriguez-Zapata M, Alvarez-Mon M, Martinez-A C, Manes S (2004) Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 200:541-47. doi:10.1084/Jem.20040061 CrossRef
  34. Giguere JF, Tremblay MJ (2004) Statin compounds reduce human immunodeficiency virus type 1 replication by preventing the interaction between virion-associated host intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1. J Virol 78:12062-2065. doi:10.1128/Jvi.78.21.12062-12065.2004 CrossRef
  
• 作者单位：Guoping Hu (1)
  Xi Li (1)
  Xianqiang Sun (1)
  Weiqiang Lu (1)
  Guixia Liu (1)
  Jin Huang (1)
  Xu Shen (2)
  Yun Tang (1)
  
  1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
  
• ISSN：0948-5023

文摘

Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, human protein Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. LEDGF/p75-HIV-1 IN interaction represents an attractive target for anti-HIV therapy. In this study, approved drugs were investigated for the finding of potential inhibitors on this target. Via molecular docking against the LEDGF/p75-binding pocket of HIV-1 IN, 26 old drugs were selected from the DrugBank and purchased for bioassays. Among them, eight, namely Atorvastatin, Bumetanide, Candesartan, Carbidopa, Diclofenac, Diflunisal, Eprosartan, and Sulindac, were identified as potential inhibitors of LEDGF/p75- HIV-1 IN interaction, whose IC50 values ranged from 6.5-em class="a-plus-plus">μM to 36.8-em class="a-plus-plus">μM. In addition, Atorvastatin was previously reported to block HIV-1 replication and may have an important implication for the treatment of AIDS. Our results suggested a mechanism of action for the anti-HIV effects of Atorvastatin. This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery.