Binding Insight of Anti-HIV Phytocompounds with Prime Targets of HIV: A Molecular Dynamics Simulation Analysis

Author(s): Jaykant Vora, Mohd Athar, Sonam Sinha, Prakash C. Jha, Neeta Shrivastava*

Journal Name: Current HIV Research

Volume 18 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Despite intense efforts, AIDS is difficult to tackle by current anti-retroviral therapy (ART) due to its side effects; therefore, there is an urgent need to discover potential, multitarget and low-cost anti-HIV compounds.

Objective: We have shown that few phytocompounds can potentially inhibit the prime targets of HIV namely GP120 envelope protein, reverse transcriptase, protease, integrase and ribonulcease. In this study, top ranked prioritized compounds were subjected to Molecular Dynamics (MD) simulation in order to study the conformational dynamics and integrity of crucial interaction in the receptor sites.

Methods: The system was built for selected protein-ligand complex using TIP3P water model and OPLS_2005 force field. Trajectories were recorded up to 20 ns simulation time in Desmond module of Schrödinger software.

Results: As a result of a comprehensive analysis of molecular properties and dynamics of the complexes, it has been concluded that Chebulic acid, Curcumin and Mulberroside C could be developed as envelope glycoprotein GP120 inhibitor, reverse transcriptase inhibitor and protease inhibitor respectively. However, the fluctuation of Chebulic acid with respect to integrase and ribonuclease protein was higher during the simulation.

Conclusion: These findings can aid in the designing of the structural properties for more effective anti-HIV compounds against the given targets.

Keywords: Molecular dynamics simulation, anti-HIV, drug discovery, natural compounds, curcumin, mulberroside C, chebulic acid.

[1]
Ode H, Nakashima M, Kitamura S, Sugiura W, Sato H. Molecular dynamics simulation in virus research. Front Microbiol 2012; 3: 258.
[http://dx.doi.org/10.3389/fmicb.2012.00258] [PMID: 22833741]
[2]
Ishima R, Torchia DA. Protein dynamics from NMR. Nat Struct Biol 2000; 7(9): 740-3.
[http://dx.doi.org/10.1038/78963] [PMID: 10966641]
[3]
Abbondanzieri EA, Bokinsky G, Rausch JW, Zhang JX, Le Grice SF, Zhuang X. Dynamic binding orientations direct activity of HIV reverse transcriptase. Nature 2008; 453(7192): 184-9.
[http://dx.doi.org/10.1038/nature06941] [PMID: 18464735]
[4]
Thorpe IF, Brooks CL III. Molecular evolution of affinity and flexibility in the immune system. Proc Natl Acad Sci USA 2007; 104(21): 8821-6.
[http://dx.doi.org/10.1073/pnas.0610064104] [PMID: 17488816]
[5]
Durrant JD, McCammon JA. Molecular dynamics simulations and drug discovery. BMC Biol 2011; 9: 71.
[http://dx.doi.org/10.1186/1741-7007-9-71] [PMID: 22035460]
[6]
Borhani DW, Shaw DE. The future of molecular dynamics simulations in drug discovery. J Comput Aided Mol Des 2012; 26(1): 15-26.
[http://dx.doi.org/10.1007/s10822-011-9517-y] [PMID: 22183577]
[7]
Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov 2018; 13(1): 23-37.
[http://dx.doi.org/10.1080/17460441.2018.1403419] [PMID: 29139324]
[8]
Salmaso V, Moro S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: An Overview. Front Pharmacol 2018; 9: 923.
[http://dx.doi.org/10.3389/fphar.2018.00923] [PMID: 30186166]
[9]
Mirani A, Kundaikar H, Velhal S, et al. Evaluation of phytopolyphenols for their gp120-CD4 binding inhibitory properties by in silico molecular modelling & in vitro cell line studies. Curr HIV Res 2019; 17(2): 102-13.
[http://dx.doi.org/10.2174/1570162X17666190611121627] [PMID: 31187713]
[10]
De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of molecular dynamics and related methods in drug discovery. J Med Chem 2016; 59(9): 4035-61.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01684] [PMID: 26807648]
[11]
Zazzi M, Cozzi-Lepri A, Prosperi MC. Computer-aided optimization of combined anti-retroviral therapy for HIV: New drugs, new drug targets and drug resistance. Curr HIV Res 2016; 14(2): 101-9.
[http://dx.doi.org/10.2174/1570162X13666151029102254] [PMID: 26511342]
[12]
Moss JA. HIV/AIDS Review. Radiol Technol 2013; 84(3): 247-67.
[PMID: 23322863]
[13]
Okoye AA, Picker LJ. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev 2013; 254(1): 54-64.
[http://dx.doi.org/10.1111/imr.12066] [PMID: 23772614]
[14]
Vidya Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE. Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. Front Immunol 2017; 8: 580.
[http://dx.doi.org/10.3389/fimmu.2017.00580] [PMID: 28588579]
[15]
Larijani MS, Ramezani A, Sadat SM. Updated Studies on the Development of HIV Therapeutic Vaccine. Curr HIV Res 2019; 17(2): 75-84.
[http://dx.doi.org/10.2174/1570162X17666190618160608] [PMID: 31210114]
[16]
Letvin NL, Bloom BR, Hoffman SL. Prospects for vaccines to protect against AIDS. Tuberculosis, and Malaria. JAMA 2001; 285(5): 606-11.
[17]
Prieto P, Podzamczer D. Switching strategies in the recent era of antiretroviral therapy. Expert Rev Clin Pharmacol 2019; 12(3): 235-47.
[http://dx.doi.org/10.1080/17512433.2019.1575728] [PMID: 30691315]
[18]
Bhattacharya J. HIV prevention & treatment strategies - Current challenges & future prospects. Indian J Med Res 2018; 148(6): 671-4.
[http://dx.doi.org/10.4103/0971-5916.252150] [PMID: 30777998]
[19]
Abah IO, Ncube NBQ, Bradley HA. AgbaJi OO, Kanki P. Antiretroviral Therapy-associated Adverse Drug Reactions and their Effects on Virologic Failure- A Retrospective Cohort Study in Nigeria. Curr HIV Res 2018; 16(6): 436-46.
[http://dx.doi.org/10.2174/1389450120666190214144609] [PMID: 30767743]
[20]
Cary DC, Peterlin BM. Natural Products and HIV/AIDS. AIDS Res Hum Retroviruses 2018; 34(1): 31-8.
[http://dx.doi.org/10.1089/aid.2017.0232] [PMID: 29226706]
[21]
Kurapati KRV, Atluri VS, Samikkannu T, Garcia G, Nair MP. Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview. Front Microbiol 2016; 6: 1444.
[http://dx.doi.org/10.3389/fmicb.2015.01444] [PMID: 26793166]
[22]
Buckheit RWJ Jr, Russell JD, Xu ZQ, Flavin M. Anti-HIV-1 activity of calanolides used in combination with other mechanistically diverse inhibitors of HIV-1 replication. Antivir Chem Chemother 2000; 11(5): 321-7.
[http://dx.doi.org/10.1177/095632020001100502] [PMID: 11142630]
[23]
Vora J, Patel S, Sinha S, et al. Molecular docking, QSAR and ADMET based mining of natural compounds against prime targets of HIV. J Biomol Struct Dyn 2019; 37(1): 131-46.
[http://dx.doi.org/10.1080/07391102.2017.1420489] [PMID: 29268664]
[24]
Zhang Y-L, Luo J-G, Wan C-X, Zhou ZB, Kong LY. Geranylated 2-arylbenzofurans from Morus alba var. tatarica and their α-glucosidase and protein tyrosine phosphatase 1B inhibitory activities. Fitoterapia 2014; 92: 116-26.
[http://dx.doi.org/10.1016/j.fitote.2013.10.017] [PMID: 24216050]
[25]
Hansawasdi C, Kawabata J. α-glucosidase inhibitory effect of mulberry (Morus alba) leaves on Caco-2. Fitoterapia 2006; 77(7-8): 568-73.
[http://dx.doi.org/10.1016/j.fitote.2006.09.003] [PMID: 17071014]
[26]
Zhang M, Wang R-R, Chen M, et al. A New Flavanone Glycoside with Anti-proliferation Activity from the Root Bark of Morus alba. Chin J Nat Med 2009; 7: 105-7.
[http://dx.doi.org/10.3724/SP.J.1009.2009.00105]
[27]
Yiemwattana I, Chaisomboon N, Jamdee K. Antibacterial and Anti-inflammatory Potential of Morus alba Stem Extract. Open Dent J 2018; 12: 265-74.
[http://dx.doi.org/10.2174/1874210601812010265] [PMID: 29760819]
[28]
Eo HJ, Park JH, Park GH, et al. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark. BMC Complement Altern Med 2014; 14: 200.
[http://dx.doi.org/10.1186/1472-6882-14-200] [PMID: 24962785]
[29]
Saranya J, Shilpa G, Raghu KG, Priya S. Morus alba Leaf Lectin (MLL) Sensitizes MCF-7 Cells to Anoikis by Inhibiting Fibronectin Mediated Integrin-FAK Signaling through Ras and Activation of P38 MAPK. Front Pharmacol 2017; 8: 34.
[http://dx.doi.org/10.3389/fphar.2017.00034] [PMID: 28223935]
[30]
Jiao Y, Wang X, Jiang X, Kong F, Wang S, Yan C. Antidiabetic effects of Morus alba fruit polysaccharides on high-fat diet- and streptozotocin-induced type 2 diabetes in rats. J Ethnopharmacol 2017; 199: 119-27.
[http://dx.doi.org/10.1016/j.jep.2017.02.003] [PMID: 28163112]
[31]
Tian S, Tang M, Zhao B. Current anti-diabetes mechanisms and clinical trials using Morus alba L. J. Tradit Chinese Med Sci 2016; 3: 3-8.
[http://dx.doi.org/10.1016/j.jtcms.2016.04.001]
[32]
Ahn E, Lee J, Jeon Y-H, Choi SW, Kim E. Anti-diabetic effects of mulberry (Morus alba L.) branches and oxyresveratrol in streptozotocin-induced diabetic mice. Food Sci Biotechnol 2017; 26(6): 1693-702.
[http://dx.doi.org/10.1007/s10068-017-0223-y] [PMID: 30263707]
[33]
Martin JL, Maldonado JO, Mueller JD, Zhang W, Mansky LM. Molecular studies of HTLV-1 replication: An update. Viruses 2016; 8(2): 1-22.
[http://dx.doi.org/10.3390/v8020031] [PMID: 26828513]
[34]
Sakagami H, Asano K, Satoh K, et al. Anti-stress, anti-HIV and vitamin C-synergized radical scavenging activity of mulberry juice fractions. In Vivo 2007; 21(3): 499-505.
[PMID: 17591360]
[35]
Praditya D, Kirchhoff L, Brüning J, Rachmawati H, Steinmann J, Steinmann E. Anti-infective Properties of the Golden Spice Curcumin. Front Microbiol 2019; 10: 912.
[http://dx.doi.org/10.3389/fmicb.2019.00912] [PMID: 31130924]
[36]
Chainani-Wu N. Safety and Anti-Inflammatory Activity of Curcumin. J Altern Complement Med 2003; 9(1): 161-8.
[37]
Marathe SA, Datey AA, Chakravortty D. Herbal Cocktail as Anti-infective: Promising Therapeutic for the Treat- ment of Viral Diseases. Recent Pat Antiinfect Drug Discov 2012; 7(2): 123-32.
[38]
Jalaluddin M, Jayanti I, Gowdar IM, Roshan R, Varkey RR, Thirutheri A. Antimicrobial Activity of Curcuma longa L. Extract on Periodontal Pathogens. J Pharm Bioallied Sci 2019; 11(Suppl. 2): S203-7.
[http://dx.doi.org/10.4103/JPBS.JPBS_295_18] [PMID: 31198338]
[39]
Afrose R, Saha SK, Banu LA, et al. Antibacterial Effect of Curcuma longa (Turmeric) Against Staphylococcus aureus and Escherichia coli. Mymensingh Med J 2015; 24(3): 506-15.
[PMID: 26329948]
[40]
Gupta A, Mahajan S, Sharma R. Evaluation of antimicrobial activity of Curcuma longa rhizome extract against Staphylococcus aureus. Biotechnol reports (Amsterdam, Netherlands) 2015; 6: 51- 5.
[http://dx.doi.org/10.1016/j.btre.2015.02.001]
[41]
Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R. Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett 1995; 94(1): 79-83.
[http://dx.doi.org/10.1016/0304-3835(95)03827-J] [PMID: 7621448]
[42]
Ak T, Gülçin I. Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 2008; 174(1): 27-37.
[http://dx.doi.org/10.1016/j.cbi.2008.05.003] [PMID: 18547552]
[43]
Jayaprakasha GK, Rao LJ, Sakariah KK. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chem 2006; 98: 720-4.
[http://dx.doi.org/10.1016/j.foodchem.2005.06.037]
[44]
Priyadarsini KI, Maity DK, Naik GH, et al. Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. Free Radic Biol Med 2003; 35(5): 475-84.
[http://dx.doi.org/10.1016/S0891-5849(03)00325-3] [PMID: 12927597]
[45]
Negrette-Guzmán M. Combinations of the antioxidants sulforaphane or curcumin and the conventional antineoplastics cisplatin or doxorubicin as prospects for anticancer chemotherapy. Eur J Pharmacol 2019; 859: 172513
[http://dx.doi.org/10.1016/j.ejphar.2019.172513] [PMID: 31260654]
[46]
Azzi E, Alberti D, Parisotto S, et al. Design, synthesis and preliminary in-vitro studies of novel boronated monocarbonyl analogues of Curcumin (BMAC) for antitumor and β-amiloyd disaggregation activity. Bioorg Chem 2019; 93: 103324
[http://dx.doi.org/10.1016/j.bioorg.2019.103324] [PMID: 31585269]
[47]
Chen S, Wu J, Tang Q, et al. Nano-micelles based on hydroxyethyl starch-curcumin conjugates for improved stability, antioxidant and anticancer activity of curcumin. Carbohydr Polym 2020; 228: 115398
[http://dx.doi.org/10.1016/j.carbpol.2019.115398] [PMID: 31635734]
[48]
Rodrigues FC, Anil Kumar NV, Thakur G. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review. Eur J Med Chem 2019; 177: 76-104.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.058] [PMID: 31129455]
[49]
Fratantonio D, Molonia MS, Bashllari R, et al. Curcumin potentiates the antitumor activity of Paclitaxel in rat glioma C6 cells. Phytomedicine 2019; 55: 23-30.
[http://dx.doi.org/10.1016/j.phymed.2018.08.009] [PMID: 30668434]
[50]
Prasad S, Tyagi AK. Curcumin and its analogues: a potential natural compound against HIV infection and AIDS. Food Funct 2015; 6(11): 3412-9.
[http://dx.doi.org/10.1039/C5FO00485C] [PMID: 26404185]
[51]
Ichsyani M, Ridhanya A, Risanti M, et al. Antiviral effects of Curcuma longa L. against dengue virus in vitro and in vivo. IOP Conf. Ser Earth Environ Sci 2017; 101: 12005.
[52]
Kumari N, Kulkarni AA, Lin X, et al. Inhibition of HIV-1 by curcumin A, a novel curcumin analog. Drug Des Devel Ther 2015; 9: 5051-60.
[PMID: 26366056]
[53]
Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed Res Int 2014; 2014: 186864
[PMID: 24877064]
[54]
Li H, Zhong C, Wang Q, Chen W, Yuan Y. Curcumin is an APE1 redox inhibitor and exhibits an antiviral activity against KSHV replication and pathogenesis. Antiviral Res 2019; 167: 98-103.
[http://dx.doi.org/10.1016/j.antiviral.2019.04.011] [PMID: 31034848]
[55]
Mounce BC, Cesaro T, Carrau L, Vallet T, Vignuzzi M. Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antiviral Res 2017; 142: 148-57.
[http://dx.doi.org/10.1016/j.antiviral.2017.03.014] [PMID: 28343845]
[56]
Oyuntsetseg N, Khasnatinov MA, Molor-Erdene P, et al. Evaluation of direct antiviral activity of the Deva-5 herb formulation and extracts of five Asian plants against influenza A virus H3N8. BMC Complement Altern Med 2014; 14: 235.
[http://dx.doi.org/10.1186/1472-6882-14-235] [PMID: 25012588]
[57]
Kesharwani A, Polachira SK, Nair R, Agarwal A, Mishra NN, Gupta SK. Anti-HSV-2 activity of Terminalia chebula Retz extract and its constituents, chebulagic and chebulinic acids. BMC Complement Altern Med 2017; 17(1): 110.
[http://dx.doi.org/10.1186/s12906-017-1620-8] [PMID: 28196487]
[58]
Filho JR, de Sousa Falcão H, Batista LM, Filho JM, Piuvezam MR. Effects of plant extracts on HIV-1 protease. Curr HIV Res 2010; 8(7): 531-44.
[http://dx.doi.org/10.2174/157016210793499204] [PMID: 20946094]
[59]
Wang M, Li Y, Hu X. Chebulinic acid derived from triphala is a promising antitumour agent in human colorectal carcinoma cell lines. BMC Complement Altern Med 2018; 18(1): 342.
[http://dx.doi.org/10.1186/s12906-018-2412-5] [PMID: 30587184]
[60]
Sivamaruthi BS, Ramkumar VS, Archunan G, et al. Biogenic synthesis of silver palladium bimetallic nanoparticles from fruit extract of Terminalia chebula – In vitro evaluation of anticancer and antimicrobial activity. J Drug Deliv Sci Technol 2019; 51: 139-51.
[http://dx.doi.org/10.1016/j.jddst.2019.02.024]
[61]
Saha S, Verma RJ. Antioxidant activity of polyphenolic extract of Terminalia chebula Retzius fruits. J Taibah Univ Sci 2016; 10: 805-12.
[http://dx.doi.org/10.1016/j.jtusci.2014.09.003]
[62]
Lee H-S, Jung S-H, Yun B-S, Lee KW. Isolation of chebulic acid from Terminalia chebula Retz. and its antioxidant effect in isolated rat hepatocytes. Arch Toxicol 2007; 81(3): 211-8.
[http://dx.doi.org/10.1007/s00204-006-0139-4] [PMID: 16932919]
[63]
Suchalatha S, Srinivasulu C, Devi S. Antioxidant activity of ethanolic extract of Terminalia chebula fruit against isoproterenol-induced oxidative stress in rats. Indian J Biochem Biophys 2005; 42(4): 246-9.
[PMID: 23923550]
[64]
Belapurkar P, Goyal P, Tiwari-Barua P. Immunomodulatory effects of triphala and its individual constituents: a review. Indian J Pharm Sci 2014; 76(6): 467-75.
[PMID: 25593379]
[65]
Rubab I, Ali S. Dried fruit extract of Terminalia chebula modulates the immune response in mice. Food Agric Immunol 2016; 27: 1-22.
[http://dx.doi.org/10.1080/09540105.2015.1055554]
[66]
Parekh J, Chanda S. Evaluation of antimicrobial activity of terminalia chebula retz. Fruit in Different Solvents. J Herbs Spices Med Plants 2008; 13: 107-16.
[http://dx.doi.org/10.1300/J044v13n02_10]
[67]
Bajpai VK, Rahman A, Shukla S, et al. In vitro kinetics and antifungal activity of various extracts of Terminalia chebula seeds against plant pathogenic fungi. Arch Phytopathol Pflanzenschutz 2010; 43: 801-9.
[http://dx.doi.org/10.1080/03235400802246887]
[68]
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]
[69]
Vora J, Patel S, Athar M, et al. Pharmacophore modeling, molecular docking and molecular dynamics simulation for screening and identifying anti-dengue phytocompounds. J Biomol Struct Dyn 2019; 1-15.
[http://dx.doi.org/10.1080/07391102.2019.1615002] [PMID: 31057055]
[70]
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 2010; 6(5): 1509-19.
[http://dx.doi.org/10.1021/ct900587b] [PMID: 26615687]
[71]
Ali A, Banerjea AC. Curcumin inhibits HIV-1 by promoting Tat protein degradation. Sci Rep 2016; 6: 27539.
[http://dx.doi.org/10.1038/srep27539] [PMID: 27283735]
[72]
Mazumder A, Raghavan K, Weinstein J, Kohn KW, Pommier Y. Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem Pharmacol 1995; 49(8): 1165-70.
[http://dx.doi.org/10.1016/0006-2952(95)98514-A] [PMID: 7748198]
[73]
Poornima CS, Dean PM. Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. J Comput Aided Mol Des 1995; 9(6): 500-12.
[http://dx.doi.org/10.1007/BF00124321] [PMID: 8789192]
[74]
Karnati KR, Wang Y. Structural and binding insights into HIV-1 protease and P2-ligand interactions through molecular dynamics simulations, binding free energy and principal component analysis. J Mol Graph Model 2019; 92: 112-22.
[http://dx.doi.org/10.1016/j.jmgm.2019.07.008] [PMID: 31351319]
[75]
Ahn M-J, Kim CY, Lee JS, et al. Inhibition of HIV-1 integrase by galloyl glucoses from Terminalia chebula and flavonol glycoside gallates from Euphorbia pekinensis. Planta Med 2002; 68(5): 457-9.
[http://dx.doi.org/10.1055/s-2002-32070] [PMID: 12058327]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 2
Year: 2020
Page: [132 - 141]
Pages: 10
DOI: 10.2174/1570162X18666200129112509
Price: $65

Article Metrics

PDF: 17
HTML: 4
EPUB: 1
PRC: 1