Evaluation of Phytopolyphenols for their gp120-CD4 Binding Inhibitory Properties by In Silico Molecular Modelling & In Vitro Cell Line Studies

Author(s): Amit Mirani , Harish Kundaikar , Shilpa Velhal , Vainav Patel , Atmaram Bandivdekar , Mariam Degani , Vandana Patravale* .

Journal Name: Current HIV Research

Volume 17 , Issue 2 , 2019

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Abstract:

Background: Lack of effective early-stage HIV-1 inhibitor instigated the need for screening of novel gp120-CD4 binding inhibitor. Polyphenols, a secondary metabolite derived from natural sources are reported to have broad spectrum HIV-1 inhibitory activity. However, the gp120-CD4 binding inhibitory activity of polyphenols has not been analysed in silico yet.

Objectives: To establish the usage of phytopolyphenols (Theaflavin, Epigallocatechin (EGCG), Ellagic acid and Gallic acid) as early stage HIV-1 inhibitor by investigating their binding mode in reported homology of gp120-CD4 receptor complex using in silico screening studies and in vitro cell line studies.

Methods: The in silico molecular docking and molecular simulation studies were performed using Schrödinger 2013-2 suite installed on Fujitsu Celsius Workstation. The in vitro cell line studies were performed in the TZM-bl cell line using MTT assay and β-galactosidase assay.

Results: The results of molecular docking indicated that Theaflavin and EGCG exhibited high XP dock score with binding pose exhibiting Van der Waals interaction and hydrophobic interaction at the deeper site in the Phe43 cavity with Asp368 and Trp427. Both Theaflavin and EGCG form a stable complex with the prepared HIV-1 receptor and their binding mode interaction is within the vicinity 4 Å. Further, in vitro cell line studies also confirmed that Theaflavin (SI = 252) and EGCG (SI = 138) exert better HIV-1 inhibitory activity as compared to Ellagic acid (SI = 30) and Gallic acid (SI = 34).

Conclusion: The results elucidate a possible binding mode of phytopolyphenols, which pinpoints their plausible mechanism and directs their usage as early stage HIV-1 inhibitor.

Keywords: In silico, molecular docking, theaflavin, EGCG, ellagic acid, gallic acid, gp120-CD4 inhibitor.

[1]
Global Report: UNAIDS Report on the Global AIDS Epidemic: 2016 [25 December 2017] http://www.refworld.org/docid/574e8 d394.html
[2]
De Cock KM, Jaffe HW, Curran JW. The evolving epidemiology of HIV/AIDS. AIDS 2012; 26(10): 1205-13.
[http://dx.doi.org/10.1097/QAD.0b013e328354622a] [PMID: 22706007]
[3]
Maartens G, Celum C, Lewin SR. HIV infection: Epidemiology, pathogenesis, treatment, and prevention. Lancet 2014; 384(9939): 258-71.
[http://dx.doi.org/10.1016/S0140-6736(14)60164-1] [PMID: 24907868]
[4]
Ariën KK, Jespers V, Vanham G. HIV sexual transmission and microbicides. Rev Med Virol 2011; 21(2): 110-33.
[http://dx.doi.org/10.1002/rmv.684] [PMID: 21412935]
[5]
Brelot A, Alizon M. HIV-1 entry and how to block it. AIDS 2001; 15(5)(Suppl. 5): S3-S11.
[http://dx.doi.org/10.1097/00002030-200100005-00002] [PMID: 11816172]
[6]
Zhang L, He T, Talal A, Wang G, Frankel SS, Ho DD. In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors: CXCR4, CCR3, and CCR5. J Virol 1998; 72(6): 5035-45.
[PMID: 9573273]
[7]
Peterman TA, Curran JW. Sexual transmission of human immunodeficiency virus. JAMA 1986; 256(16): 2222-6.
[http://dx.doi.org/10.1001/jama.1986.03380160080024] [PMID: 3531561]
[8]
Hladik F, Sakchalathorn P, Ballweber L, et al. Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1. Immunity 2007; 26(2): 257-70.
[http://dx.doi.org/10.1016/j.immuni.2007.01.007] [PMID: 17306567]
[9]
Malik T, Chauhan G, Rath G, Murthy RSR, Goyal AK. “Fusion and binding inhibition” key target for HIV-1 treatment and pre-exposure prophylaxis: Targets, drug delivery and nanotechnology approaches. Drug Deliv 2017; 24(1): 608-21.
[http://dx.doi.org/10.1080/10717544.2016.1228717] [PMID: 28240046]
[10]
Lasky LA, Nakamura G, Smith DH, et al. Delineation of a region of the human immunodeficiency virus type 1 gp120 glycoprotein critical for interaction with the CD4 receptor. Cell 1987; 50(6): 975-85.
[http://dx.doi.org/10.1016/0092-8674(87)90524-1] [PMID: 2441877]
[11]
Weiss RA, Clapham PR, Weber JN, Dalgleish AG, Lasky LA, Berman PW. Variable and conserved neutralization antigens of human immunodeficiency virus. Nature 1986; 324(6097): 572-5.
[http://dx.doi.org/10.1038/324572a0] [PMID: 2431324]
[12]
Willey RL, Rutledge RA, Dias S, et al. Identification of conserved and divergent domains within the envelope gene of the acquired immunodeficiency syndrome retrovirus. Proc Natl Acad Sci USA 1986; 83(14): 5038-42.
[http://dx.doi.org/10.1073/pnas.83.14.5038] [PMID: 3014529]
[13]
Schames JR, Henchman RH, Siegel JS, Sotriffer CA, Ni H, McCammon JA. Discovery of a novel binding trench in HIV integrase. J Med Chem 2004; 47(8): 1879-81.
[http://dx.doi.org/10.1021/jm0341913] [PMID: 15055986]
[14]
Kong R, Tan JJ, Ma XH, Chen WZ, Wang CX. Prediction of the binding mode between BMS-378806 and HIV-1 gp120 by docking and molecular dynamics simulation. Biochim Biophys Acta 2006; 1764(4): 766-72.
[http://dx.doi.org/10.1016/j.bbapap.2005.12.017] [PMID: 16455315]
[15]
Sivan SK, Vangala R, Manga V. Molecular docking guided structure based design of symmetrical N,N′-disubstituted urea/thiourea as HIV-1 gp120-CD4 binding inhibitors. Bioorg Med Chem 2013; 21(15): 4591-9.
[http://dx.doi.org/10.1016/j.bmc.2013.05.038] [PMID: 23777826]
[16]
Narumi T, Arai H, Yoshimura K, et al. Small molecular CD4 mimics as HIV entry inhibitors. Bioorg Med Chem 2011; 19(22): 6735-42.
[http://dx.doi.org/10.1016/j.bmc.2011.09.045] [PMID: 22014753]
[17]
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393(6686): 648-59.
[http://dx.doi.org/10.1038/31405] [PMID: 9641677]
[18]
Moebius U, Clayton LK, Abraham S, Harrison SC, Reinherz EL. The human immunodeficiency virus gp120 binding site on CD4: Delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure. J Exp Med 1992; 176(2): 507-17.
[http://dx.doi.org/10.1084/jem.176.2.507] [PMID: 1500858]
[19]
Sweet RW, Truneh A, Hendrickson WA. CD4: Its structure, role in immune function and AIDS pathogenesis, and potential as a pharmacological target. Curr Opin Biotechnol 1991; 2(4): 622-33.
[http://dx.doi.org/10.1016/0958-1669(91)90089-N] [PMID: 1367682]
[20]
Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 2006; 57(4): 619-27.
[http://dx.doi.org/10.1093/jac/dkl027] [PMID: 16464888]
[21]
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393(6686): 648-59.
[http://dx.doi.org/10.1038/31405] [PMID: 9641677]
[22]
Shrivastava I, LaLonde JM. Enhanced dynamics of HIV gp120 glycoprotein by small molecule binding. Biochemistry 2011; 50(19): 4173-83.
[http://dx.doi.org/10.1021/bi2002218] [PMID: 21488663]
[23]
Tsou LK, Chen CH, Dutschman GE, Cheng YC, Hamilton AD. Blocking HIV-1 entry by a gp120 surface binding inhibitor. Bioorg Med Chem Lett 2012; 22(9): 3358-61.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.079] [PMID: 22487177]
[24]
Liu T, Huang B, Zhan P, De Clercq E, Liu X. Discovery of small molecular inhibitors targeting HIV-1 gp120-CD4 interaction drived from BMS-378806. Eur J Med Chem 2014; 86: 481-90.
[http://dx.doi.org/10.1016/j.ejmech.2014.09.012] [PMID: 25203778]
[25]
Curreli F, Kwon YD, Zhang H, et al. Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-Ray structure and resistance study. Antimicrob Agents Chemother 2014; 58(9): 5478-91.
[http://dx.doi.org/10.1128/AAC.03339-14] [PMID: 25001301]
[26]
Date AA, Destache CJ. Natural polyphenols: Potential in the prevention of sexually transmitted viral infections. Drug Discov Today 2016; 21(2): 333-41.
[http://dx.doi.org/10.1016/j.drudis.2015.10.019] [PMID: 26546859]
[27]
Andrae-Marobela K, Ghislain FW, Okatch H, et al. Polyphenols: A diverse class of multi-target anti-HIV-1 agents. Curr Drug Metab 2013; 14: 392-413.
[http://dx.doi.org/10.2174/13892002113149990095]
[28]
Narayan LC, Rai VR, Tewtrakul S. Emerging need to use phytopharmaceuticals in the treatment of HIV. J Pharm Res 2013; 6: 218-23.
[http://dx.doi.org/10.1016/j.jopr.2012.11.002]
[29]
Farzaei MH, Rahimi R, Abdollahi M. The role of dietary polyphenols in the management of inflammatory bowel disease. Curr Pharm Biotechnol 2015; 16(3): 196-210.
[http://dx.doi.org/10.2174/1389201016666150118131704] [PMID: 25601607]
[30]
Scalbert A, Manach C, Morand C, Rémésy C, Jiménez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr 2005; 45(4): 287-306.
[http://dx.doi.org/10.1080/1040869059096] [PMID: 16047496]
[31]
Khan N, Mukhtar H. Tea polyphenols for health promotion. Life Sci 2007; 81(7): 519-33.
[http://dx.doi.org/10.1016/j.lfs.2007.06.011] [PMID: 17655876]
[32]
Ramassamy C. Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets. Eur J Pharmacol 2006; 545(1): 51-64.
[http://dx.doi.org/10.1016/j.ejphar.2006.06.025] [PMID: 16904103]
[33]
Hartjen P, Frerk S, Hauber I, et al. Assessment of the range of the HIV-1 infectivity enhancing effect of individual human semen specimen and the range of inhibition by EGCG. AIDS Res Ther 2012; 9(1): 2.
[http://dx.doi.org/10.1186/1742-6405-9-2] [PMID: 22260499]
[34]
Hauber I, Hohenberg H, Holstermann B, Hunstein W, Hauber J. The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection. Proc Natl Acad Sci USA 2009; 106(22): 9033-8.
[http://dx.doi.org/10.1073/pnas.0811827106] [PMID: 19451623]
[35]
Williamson MP, McCormick TG, Nance CL, Shearer WT. Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy. J Allergy Clin Immunol 2006; 118(6): 1369-74.
[http://dx.doi.org/10.1016/j.jaci.2006.08.016] [PMID: 17157668]
[36]
Nance CL, Siwak EB, Shearer WT. Preclinical development of the green tea catechin, epigallocatechin gallate, as an HIV-1 therapy. J Allergy Clin Immunol 2009; 123(2): 459-65.
[http://dx.doi.org/10.1016/j.jaci.2008.12.024] [PMID: 19203663]
[37]
Liu S, Lu H, Zhao Q, et al. Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry by targeting gp41. Biochim Biophys Acta 2005; 1723(1-3): 270-81.
[http://dx.doi.org/10.1016/j.bbagen.2005.02.012] [PMID: 15823507]
[38]
Guo J, Xu X, Rasheed TK, et al. Genistein interferes with SDF-1- and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells. Retrovirology 2013; 10: 62.
[http://dx.doi.org/10.1186/1742-4690-10-62] [PMID: 23782904]
[39]
Sauter D, Schwarz S, Wang K, Zhang R, Sun B, Schwarz W. Genistein as antiviral drug against HIV ion channel. Planta Med 2014; 80(8-9): 682-7.
[http://dx.doi.org/10.1055/s-0034-1368583] [PMID: 24963618]
[40]
Promsong A, Chuenchitra T, Saipin K, et al. Ellagic acid inhibits HIV-1 infection in vitro: Potential role as a novel microbicide. Oral Dis 2018; 24(1-2): 249-52.
[http://dx.doi.org/10.1111/odi.12835] [PMID: 29480632]
[41]
Modi M, Goel T, Das T, et al. Ellagic acid & gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activity. Indian J Med Res 2013; 137(3): 540-8.
[PMID: 23640562]
[42]
Huang CC, Venturi M, Majeed S, et al. Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci USA 2004; 101(9): 2706-11.
[http://dx.doi.org/10.1073/pnas.0308527100] [PMID: 14981267]
[43]
LigPrep, version 26. New York, NY: Schrödinger, LLC 2013.
[44]
Glide, version 59. New York: Schrödinger, LLC 2013.
[45]
QikProp, version 36 New York, NY: Schrödinger, LLC. 2013.
[46]
Molecular D. Desmond Molecular Dynamics System, version 34. New York, NY: D.E. Shaw Research 2013.
[47]
Banks JL, Beard HS, Cao Y, et al. Integrated Modeling Program, Applied Chemical Theory (IMPACT). J Comput Chem 2005; 26(16): 1752-80.
[http://dx.doi.org/10.1002/jcc.20292] [PMID: 16211539]
[48]
Berendsen HJC, Postma JPM, van Gunsteren WF. Interaction models for water in relation to protein hydration In: Pullman B, Ed. Intermolecular forces: Proceedings of the Fourteenth Jerusalem Symposium on Quantum Chemistry and Biochemistry. 1981; pp. 331-42.
[http://dx.doi.org/10.1007/978-94-015-7658-1_21]
[49]
Essmann U, Perera L, Berkowitz ML. A smooth particle mesh Ewald method. J Chem Phys 1995; 103: 8577.
[http://dx.doi.org/10.1063/1.470117]
[50]
Uttekar MM, Das T, Pawar RS, et al. Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding. Eur J Med Chem 2012; 56: 368-74.
[http://dx.doi.org/10.1016/j.ejmech.2012.07.030] [PMID: 22858223]
[51]
Neurath AR, Strick N, Li YY, Debnath AK. Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide. BMC Infect Dis 2004; 4: 41-53.
[http://dx.doi.org/10.1186/1471-2334-4-41] [PMID: 15485580]
[52]
Kwong PD, Wyatt R, Majeed S, et al. Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates. Structure 2000; 8(12): 1329-39.
[http://dx.doi.org/10.1016/S0969-2126(00)00547-5] [PMID: 11188697]
[53]
Wyatt R, Kwong PD, Desjardins E, et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 1998; 393(6686): 705-11.
[http://dx.doi.org/10.1038/31514] [PMID: 9641684]
[54]
Tsou LK, Cheng Y, Cheng YC. Therapeutic development in targeting protein-protein interactions with synthetic topological mimetics. Curr Opin Pharmacol 2012; 12(4): 403-7.
[http://dx.doi.org/10.1016/j.coph.2012.04.004] [PMID: 22578832]
[55]
Kadow J, Wang HG, Lin PF. Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development. Curr Opin Investig Drugs 2006; 7(8): 721-6.
[PMID: 16955683]
[56]
Lin PF, Blair W, Wang T, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA 2003; 100(19): 11013-8.
[http://dx.doi.org/10.1073/pnas.1832214100] [PMID: 12930892]
[57]
Si Z, Madani N, Cox JM, et al. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci USA 2004; 101(14): 5036-41.
[http://dx.doi.org/10.1073/pnas.0307953101] [PMID: 15051887]
[58]
Ho HT, Fan L, Nowicka-Sans B, et al. Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events. J Virol 2006; 80(8): 4017-25.
[http://dx.doi.org/10.1128/JVI.80.8.4017-4025.2006] [PMID: 16571818]
[59]
Zhao Q, Ma L, Jiang S, et al. 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 2005; 339(2): 213-25.
[http://dx.doi.org/10.1016/j.virol.2005.06.008] [PMID: 15996703]


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