Computational Prospecting for the Pharmacological Mechanism of Activity: HIV-1 Inhibition by Ixoratannin A-2

Author(s): Olujide O. Olubiyi*, Thomas O. Idowu, Abiodun O. Ogundaini, Goodness Orhuah

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 4 , 2020


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Abstract:

Background: Ixora coccinea is a tropical ornamental shrub employed in ethnomedicine for the treatment of a number of diseases none of which include the Human Immunodeficiency Virus (HIV) infection. Ixoratannin A-2, one of the constituents, was previously identified via virtual-screening and experimentally confirmed to possess significant anti-HIV-1 activity in an in vitro CD4+ replication assay. This activity was observed to be significantly reduced in degree in viruses lacking the protein Vpu. This suggests the involvement of Vpu as well as other extra-Vpu macromolecules in its antiviral activity.

Methods: In the present computational search for the identity of the other macromolecules that could possibly explain the observed activity, a panel of fourteen established HIV-1 macromolecular targets was assembled against which ixoratannin A-2 and other major phytoconstituents of I. coccinea were virtually screened.

Results: Structural analyses of the computed ligand-bound complexes, as well as the careful investigation of the thermodynamic attributes of the predicted binding, revealed subtle selectivity patterns at the atomistic level that suggest the likely involvement of multiple macromolecular processes. Some of the binding interactions were found to be thermodynamically favourable, including the multidrug-resistant HIV protease enzyme, CXCR4 and the human elongin C protein all of which formed reasonably strong interactions with ixoratannin A-2 and other constituents of I. coccinea.

Conclusion: Ixoratannin A-2’s ability to favourably interact with multiple HIV-1 and human targets could explain its observed extra-Vpu antiviral activity. This, however, does not imply uncontrolled binding with all available targets; on the other hand, molecular size of ixoratannin A-2 and combination of functional groups confer on it a decent level of selectivity against many of the investigated HIV/AIDS targets.

Keywords: Ixoratannin A-2, HIV1/AIDS, docking, molecular dynamics, ixora coccinea, CD4+.

[1]
Shafer, R.W.; Schapiro, J.M. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev., 2008, 10(2), 67-84.
[PMID: 18615118]
[2]
Mugomeri, E.; Chatanga, P.; Chakane, N. Medicinal herbs used by HIV-positive people in Lesotho. Afr. J. Tradit. Complement. Altern. Med., 2016, 13(4), 123-131.
[http://dx.doi.org/10.21010/ajtcam.v13i4.17] [PMID: 28852728]
[3]
Vermani, K.; Garg, S. Herbal medicines for sexually transmitted diseases and AIDS. J. Ethnopharmacol., 2002, 80(1), 49-66.
[http://dx.doi.org/10.1016/S0378-8741(02)00009-0] [PMID: 11891087]
[4]
Chinsembu, K.; Hedimbi, M. Ethnomedicinal plants and other natural products with anti-HIV active compounds and their putative modes of action. Int. J. Biotechnol. Mol. Biol. Res., 2010, 1, 74-91.
[5]
World Health Organization. In vitro screening of traditional medicines for anti-HIV Activity: memorandum from a WHO meeting. Bull. World Health Organ., 1989, 67, 613-618.
[6]
World Health Organization. Report of a WHO informal consultation on traditional medicine and AIDS: In vitro screening for anti- HIV activity, Geneva, 6-8 February 1989.
[7]
World Health Organization. WHO traditional medicine strategy 2002-2005 2002.
[8]
Asres, K.; Bucar, F.; Kartnig, T.; Witvrouw, M.; Pannecouque, C.; De Clercq, E. Antiviral activity against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) of ethnobotanically selected Ethiopian medicinal plants. Phytother. Res., 2001, 15(1), 62-69.
[http://dx.doi.org/10.1002/1099-1573(200102)15:1<62::AIDPTR956>3.0.CO;2-X] [PMID: 11180526]
[9]
Fabricant, D.S.; Farnsworth, N.R. The value of plants used in traditional medicine for drug discovery. Environ. Health Perspect., 2001, 109(Suppl. 1), 69-75.
[PMID: 11250806]
[10]
Farnsworth, N.R. Ethnopharmacology and drug development, in Ciba Foundation Symposium 185 - Ethnobotany and the search for new drugs Eds Chadwick, D.J. Marsh, J. Hoboken. 2007, pp. 42-59.
[11]
Vo, T.S.; Kim, S.K. Potential anti-HIV agents from marine resources: an overview. Mar. Drugs, 2010, 8(12), 2871-2892.
[http://dx.doi.org/10.3390/md8122871] [PMID: 21339954]
[12]
Jiang, Y.; Ng, T.B.; Wang, C.R.; Zhang, D.; Cheng, Z.H.; Liu, Z.K.; Qiao, W.T.; Geng, Y.Q.; Li, N.; Liu, F. Inhibitors from natural products to HIV-1 reverse transcriptase, protease and integrase. Mini Rev. Med. Chem., 2010, 10(14), 1331-1344.
[http://dx.doi.org/10.2174/138955710793564133] [PMID: 21175425]
[13]
Filho, J.R.; de Sousa Falcão, H.; Batista, L.M.; Filho, J.M.; Piuvezam, M.R. Effects of plant extracts on HIV-1 protease. Curr. HIV Res., 2010, 8(7), 531-544.
[http://dx.doi.org/10.2174/157016210793499204] [PMID: 20946094]
[14]
Park, I.W.; Han, C.; Song, X.; Green, L.A.; Wang, T.; Liu, Y.; Cen, C.; Song, X.; Yang, B.; Chen, G.; He, J.J. Inhibition of HIV-1 entry by extracts derived from traditional Chinese medicinal herbal plants. BMC Complement. Altern. Med., 2009, 9, 29.
[http://dx.doi.org/10.1186/1472-6882-9-29] [PMID: 19656383]
[15]
Singh, I.P.; Bodiwala, H.S. Recent advances in anti-HIV natural products. Nat. Prod. Rep., 2010, 27(12), 1781-1800.
[http://dx.doi.org/10.1039/c0np00025f] [PMID: 20976350]
[16]
Asres, K.; Seyoum, A.; Veeresham, C.; Bucar, F.; Gibbons, S. Naturally derived anti-HIV agents. Phytother. Res., 2005, 19(7), 557-581.
[http://dx.doi.org/10.1002/ptr.1629] [PMID: 16161055]
[17]
Balestrieri, E.; Pizzimenti, F.; Ferlazzo, A.; Giofrè, S.V.; Iannazzo, D.; Piperno, A.; Romeo, R.; Chiacchio, M.A.; Mastino, A.; Macchi, B. Antiviral activity of seed extract from Citrus bergamia towards human retroviruses. Bioorg. Med. Chem., 2011, 19(6), 2084-2089.
[http://dx.doi.org/10.1016/j.bmc.2011.01.024] [PMID: 21334901]
[18]
Kashiwada, Y.; Hashimoto, F.; Cosentino, L.M.; Chen, C.H.; Garrett, P.E.; Lee, K.H. Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents. J. Med. Chem., 1996, 39(5), 1016-1017.
[http://dx.doi.org/10.1021/jm950922q] [PMID: 8676334]
[19]
Qian, K.; Yu, D.; Chen, C.H.; Huang, L.; Morris-Natschke, S.L.; Nitz, T.J.; Salzwedel, K.; Reddick, M.; Allaway, G.P.; Lee, K.H. Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents. J. Med. Chem., 2009, 52(10), 3248-3258.
[http://dx.doi.org/10.1021/jm900136j] [PMID: 19388685]
[20]
Kanamoto, T.; Kashiwada, Y.; Kanbara, K.; Gotoh, K.; Yoshimori, M.; Goto, T.; Sano, K.; Nakashima, H. Anti-human immunodeficiency virus activity of YK-FH312 (a betulinic acid derivative), a novel compound blocking viral maturation. Antimicrob. Agents Chemother., 2001, 45(4), 1225-1230.
[http://dx.doi.org/10.1128/AAC.45.4.1225-1230.2001] [PMID: 11257038]
[21]
Smith, P.F.; Ogundele, A.; Forrest, A.; Wilton, J.; Salzwedel, K.; Doto, J.; Allaway, G.P.; Martin, D.E. Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-o-(3′,3′-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection. Antimicrob. Agents Chemother., 2007, 51(10), 3574-3581.
[http://dx.doi.org/10.1128/AAC.00152-07] [PMID: 17638699]
[22]
Sun, I.C.; Chen, C.H.; Kashiwada, Y.; Wu, J.H.; Wang, H.K.; Lee, K.H. Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid. J. Med. Chem., 2002, 45(19), 4271-4275.
[http://dx.doi.org/10.1021/jm020069c] [PMID: 12213068]
[23]
Wang, R.R.; Gu, Q.; Yang, L.M.; Chen, J.J.; Li, S.Y.; Zheng, Y.T. Anti-HIV-1 activities of extracts from the medicinal plant Rhus chinensis. J. Ethnopharmacol., 2006, 105(1-2), 269-273.
[http://dx.doi.org/10.1016/j.jep.2005.11.008] [PMID: 16368204]
[24]
Chen, X.; Yang, L.; Zhang, N.; Turpin, J.A.; Buckheit, R.W.; Osterling, C.; Oppenheim, J.J.; Howard, O.M. Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrob. Agents Chemother., 2003, 47(9), 2810-2816.
[http://dx.doi.org/10.1128/AAC.47.9.2810-2816.2003] [PMID: 12936978]
[25]
Han, H.; He, W.; Wang, W.; Gao, B. Inhibitory effect of aqueous Dandelion extract on HIV-1 replication and reverse transcriptase activity. BMC Complement. Altern. Med., 2011, 11, 112.
[http://dx.doi.org/10.1186/1472-6882-11-112] [PMID: 22078030]
[26]
Vlietinck, A.J.; De Bruyne, T.; Apers, S.; Pieters, L.A. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection. Planta Med., 1998, 64(2), 97-109.
[http://dx.doi.org/10.1055/s-2006-957384] [PMID: 9525100]
[27]
Dharmaratne, H.R.W.; Tan, G.T.; Marasinghe, G.P.K.; Pezzuto, J.M. Inhibition of HIV-1 reverse transcriptase and HIV-1 replication by Calophyllum coumarins and xanthones. Planta Med., 2002, 68(1), 86-87.
[http://dx.doi.org/10.1055/s-2002-20058] [PMID: 11842340]
[28]
Lee, T.T-Y.; Kashiwada, Y.; Huang, L.; Snider, J.; Cosentino, M.; Lee, K-H. Suksdorfin: an anti-HIV principle from Lomatium suksdorfii, its structure-activity correlation with related coumarins, and synergistic effects with anti-AIDS nucleosides. Bioorg. Med. Chem., 1994, 2(10), 1051-1056.
[http://dx.doi.org/10.1016/S0968-0896(00)82054-4] [PMID: 7773621]
[29]
Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S.L.; Lee, K-H. Recent progress in the development of coumarin derivatives as potent anti-HIV agents. Med. Res. Rev., 2003, 23(3), 322-345.
[http://dx.doi.org/10.1002/med.10034] [PMID: 12647313]
[30]
Zhou, P.; Takaishi, Y.; Duan, H.; Chen, B.; Honda, G.; Itoh, M.; Takeda, Y.; Kodzhimatov, O.K.; Lee, K.H. Coumarins and bicoumarin from Ferula sumbul: anti-HIV activity and inhibition of cytokine release. Phytochemistry, 2000, 53(6), 689-697.
[http://dx.doi.org/10.1016/S0031-9422(99)00554-3] [PMID: 10746882]
[31]
Tietjen, I.; Ntie-Kang, F.; Mwimanzi, P.; Onguéné, P.A.; Scull, M.A.; Idowu, T.O.; Ogundaini, A.O.; Meva’a, L.M.; Abegaz, B.M.; Rice, C.M.; Andrae-Marobela, K.; Brockman, M.A.; Brumme, Z.L.; Fedida, D. Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors. PLoS One, 2015, 10(4)e0121099
[http://dx.doi.org/10.1371/journal.pone.0121099]] [PMID: 25830320]
[32]
Saha, M.R.; Alam, M.A.; Akter, R.; Jahangir, R. In-vitro free radical scavenging activity of Ixora coccinea L. Bangladesh J. Pharmacol., 2008, 3, 90-96.
[http://dx.doi.org/10.3329/bjp.v3i2.838]
[33]
Batugal, P.A. Inventory and documentation of medicinal plants in 14 Asia Pacific countries.Medicinal Plants Research. In: Asia: The Framework And Project Work Plans, 1; Batugal, P.A.; Jayashree, K.; Lee, S.Y.; Jeffrey, T.O., Eds.; International Plant Genetic Resources Institute-Regional Office For Asia, The Pacific And Oceania: Serdang, 2004, pp. 3-6.
[34]
Nayak, B.S.; Udupa, A.L.; Udupa, S.L. Effect of Ixora coccinea flowers on dead space wound healing in rats. Fitoterapia, 1999, 70(3), 233-236.
[http://dx.doi.org/10.1016/S0367-326X(99)00025-8]
[35]
Idowu, T.O.; Ogundaini, A.O.; Salau, A.O.; Obuotor, E.M.; Bezabih, M.; Abegaz, B.M. Doubly linked, A-type proanthocyanidin trimer and other constituents of Ixora coccinea leaves and their antioxidant and antibacterial properties. Phytochemistry, 2010, 71(17-18), 2092-2098.
[http://dx.doi.org/10.1016/j.phytochem.2010.08.018] [PMID: 20843529]
[36]
Davies, D.R. The structure and function of the aspartic proteinases. Annu. Rev. Biophys. Biophys. Chem., 1990, 19(1), 189-215.
[http://dx.doi.org/10.1146/annurev.bb.19.060190.001201] [PMID: 2194475]
[37]
Brik, A.; Wong, C.H. HIV-1 protease: mechanism and drug discovery. Org. Biomol. Chem., 2003, 1(1), 5-14.
[http://dx.doi.org/10.1039/b208248a] [PMID: 12929379]
[38]
Huang, X.; Britto, M.D.; Kear-Scott, J.L.; Boone, C.D.; Rocca, J.R.; Simmerling, C.; Mckenna, R.; Bieri, M.; Gooley, P.R.; Dunn, B.M.; Fanucci, G.E. The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics. J. Biol. Chem., 2014, 289(24), 17203-17214.
[http://dx.doi.org/10.1074/jbc.M114.571836] [PMID: 24742668]
[39]
Curtis, B.M.; Scharnowske, S.; Watson, A.J. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA, 1992, 89(17), 8356-8360.
[http://dx.doi.org/10.1073/pnas.89.17.8356] [PMID: 1518869]
[40]
Dalgleish, A.G.; Beverley, P.C.; Clapham, P.R.; Crawford, D.H.; Greaves, M.F.; Weiss, R.A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature, 1984, 312(5996), 763-767.
[http://dx.doi.org/10.1038/312763a0] [PMID: 6096719]
[41]
Fiorentini, S.; Marini, E.; Caracciolo, S.; Caruso, A. Functions of the HIV-1 matrix protein p17. New Microbiol., 2006, 29(1), 1-10.
[PMID: 16608119]
[42]
Klarmann, G.J.; Hawkins, M.E.; Le Grice, S.F. Uncovering the complexities of retroviral ribonuclease H reveals its potential as a therapeutic target. AIDS Rev., 2002, 4(4), 183-194.
[PMID: 12555693]
[43]
Tramontano, E.; Di Santo, R. HIV-1 RT-associated RNase H function inhibitors: recent advances in drug development. Curr. Med. Chem., 2010, 17(26), 2837-2853.
[http://dx.doi.org/10.2174/092986710792065045] [PMID: 20858167]
[44]
Stanley, B.J.; Ehrlich, E.S.; Short, L.; Yu, Y.; Xiao, Z.; Yu, X.F.; Xiong, Y. Structural insight into the human immunodeficiency virus Vif SOCS box and its role in human E3 ubiquitin ligase assembly. J. Virol., 2008, 82(17), 8656-8663.
[http://dx.doi.org/10.1128/JVI.00767-08] [PMID: 18562529]
[45]
Miller, J.H.; Presnyak, V.; Smith, H.C. The dimerization domain of HIV-1 viral infectivity factor Vif is required to block APOBEC3G incorporation with virions. Retrovirology, 2007, 4(1), 81.
[http://dx.doi.org/10.1186/1742-4690-4-81] [PMID: 18036235]
[46]
Moriuchi, M.; Moriuchi, H.; Turner, W.; Fauci, A.S. Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry. J. Immunol., 1997, 159(9), 4322-4329.
[PMID: 9379028]
[47]
Caruz, A.; Samsom, M.; Alonso, J.M.; Alcami, J.; Baleux, F.; Virelizier, J.L.; Parmentier, M.; Arenzana-Seisdedos, F. Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett., 1998, 426(2), 271-278.
[http://dx.doi.org/10.1016/S0014-5793(98)00359-7] [PMID: 9599023]
[48]
Pavlasova, G.; Borsky, M.; Seda, V.; Cerna, K.; Osickova, J.; Doubek, M.; Mayer, J.; Calogero, R.; Trbusek, M.; Pospisilova, S.; Davids, M.S.; Kipps, T.J.; Brown, J.R.; Mraz, M. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood, 2016, 128(12), 1609-1613.
[http://dx.doi.org/10.1182/blood-2016-04-709519] [PMID: 27480113]
[49]
Saini, V.; Marchese, A.; Majetschak, M. CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin. J. Biol. Chem., 2010, 285(20), 15566-15576.
[http://dx.doi.org/10.1074/jbc.M110.103408] [PMID: 20228059]
[50]
de Silva, E.; Stumpf, M.P. HIV and the CCR5-Delta32 resistance allele. FEMS Microbiol. Lett., 2004, 241(1), 1-12.
[http://dx.doi.org/10.1016/j.femsle.2004.09.040] [PMID: 15556703]
[51]
Hütter, G.; Nowak, D.; Mossner, M.; Ganepola, S.; Müssig, A.; Allers, K.; Schneider, T.; Hofmann, J.; Kücherer, C.; Blau, O.; Blau, I.W.; Hofmann, W.K.; Thiel, E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med., 2009, 360(7), 692-698.
[http://dx.doi.org/10.1056/NEJMoa0802905] [PMID: 19213682]
[52]
Allers, K.; Hütter, G.; Hofmann, J.; Loddenkemper, C.; Rieger, K.; Thiel, E.; Schneider, T. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood, 2011, 117(10), 2791-2799.
[http://dx.doi.org/10.1182/blood-2010-09-309591] [PMID: 21148083]
[53]
Zhen, A.; Kitchen, S. Stem-cell-based gene therapy for HIV infection. Viruses, 2013, 6(1), 1-12.
[http://dx.doi.org/10.3390/v6010001] [PMID: 24368413]
[54]
Santos-Martins, D.; Forli, S.; Ramos, M.J.; Olson, A.J. AutoDock4(Zn): an improved AutoDock force field for small-molecule docking to zinc metalloproteins. J. Chem. Inf. Model., 2014, 54(8), 2371-2379.
[http://dx.doi.org/10.1021/ci500209e] [PMID: 24931227]
[55]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[56]
Goodsell, D.S.; Morris, G.M.; Olson, A.J. Automated docking of flexible ligands: applications of AutoDock. J. Mol. Recognit., 1996, 9(1), 1-5.
[http://dx.doi.org/10.1002/(SICI)1099-1352(199601)9:1<1:AID-JMR241>3.0.CO;2-6] [PMID: 8723313]
[57]
Zimmermann, G.R.; Lehár, J.; Keith, C.T. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today, 2007, 12(1-2), 34-42.
[http://dx.doi.org/10.1016/j.drudis.2006.11.008] [PMID: 17198971]
[58]
Xie, L.; Xie, L.; Kinnings, S.L.; Bourne, P.E. Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Annu. Rev. Pharmacol. Toxicol., 2012, 52, 361-379.
[http://dx.doi.org/10.1146/annurev-pharmtox-010611-134630] [PMID: 22017683]
[59]
Koeberle, A.; Werz, O. Multi-target approach for natural products in inflammation. Drug Discov. Today, 2014, 19(12), 1871-1882.
[http://dx.doi.org/10.1016/j.drudis.2014.08.006] [PMID: 25172801]
[60]
Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today, 2004, 9(15), 641-651.
[http://dx.doi.org/10.1016/S1359-6446(04)03163-0] [PMID: 15279847]
[61]
Yildirim, M.A.; Goh, K.I.; Cusick, M.E.; Barabási, A.L.; Vidal, M. Drug-target network. Nat. Biotechnol., 2007, 25(10), 1119-1126.
[http://dx.doi.org/10.1038/nbt1338] [PMID: 17921997]
[62]
Roth, B.L.; Sheffler, D.J.; Kroeze, W.K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov., 2004, 3(4), 353-359.
[http://dx.doi.org/10.1038/nrd1346] [PMID: 15060530]
[63]
Catterall, W.A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron, 2000, 26(1), 13-25.
[http://dx.doi.org/10.1016/S0896-6273(00)81133-2] [PMID: 10798388]
[64]
Hopkins, A.L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[65]
Talevi, A.; Bellera, C.L.; Di Ianni, M.; Gantner, M.; Bruno-Blanch, L.E.; Castro, E.A. CNS drug development - lost in translation? Mini Rev. Med. Chem., 2012, 12(10), 959-970.
[http://dx.doi.org/10.2174/138955712802762356] [PMID: 22420574]
[66]
Zhan, P.; Pannecouque, C.; De Clercq, E.; Liu, X. Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends. J. Med. Chem., 2016, 59(7), 2849-2878.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00497] [PMID: 26509831]
[67]
Zheng, H.; Fridkin, M.; Youdim, M. From single target to multitarget/network therapeutics in Alzheimer’s therapy. Pharmaceuticals (Basel), 2014, 7(2), 113-135.
[http://dx.doi.org/10.3390/ph7020113] [PMID: 24463342]
[68]
Talevi, A.; Bruno-Blanch, L.E. “On the development of new antiepileptic drugs for the treatment of pharmacoresistant epilepsy: different approaches to different hypothesis,” in Pharmacoresistance in Epilepsy: From Genes and Molecules to Promising Therapies; Rocha, L.; Cavalheiro, E.A., Eds.; Springer: New York, 2013, pp. 207-224.
[69]
Li, K.; Schurig-Briccio, L.A.; Feng, X.; Upadhyay, A.; Pujari, V.; Lechartier, B.; Fontes, F.L.; Yang, H.; Rao, G.; Zhu, W.; Gulati, A.; No, J.H.; Cintra, G.; Bogue, S.; Liu, Y.L.; Molohon, K.; Orlean, P.; Mitchell, D.A.; Freitas-Junior, L.; Ren, F.; Sun, H.; Jiang, T.; Li, Y.; Guo, R.T.; Cole, S.T.; Gennis, R.B.; Crick, D.C.; Oldfield, E. Multitarget drug discovery for tuberculosis and other infectious diseases. J. Med. Chem., 2014, 57(7), 3126-3139.
[http://dx.doi.org/10.1021/jm500131s] [PMID: 24568559]


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VOLUME: 16
ISSUE: 4
Year: 2020
Published on: 02 September, 2020
Page: [376 - 388]
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DOI: 10.2174/1573409915666190702111023
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