Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases

References

• Medina-FrancoJL, GiulianottiMA, WelmakerGS, HoughtenRA. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov Today. 2013;18(9–10):495–501. doi:10.1016/j.drudis.2013.01.00823340113
   PubMed Web of Science ®Google Scholar
• RamsayRR, Popovic-NikolicMR, NikolicK, UliassiE, BolognesiML. A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med. 2018;7(1). doi:10.1186/s40169-017-0181-2
   PubMed Web of Science ®Google Scholar
• BrasnyóP, MolnárGA, MohásM, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011;106(3):383–389. doi:10.1017/S000711451100031621385509
   PubMed Web of Science ®Google Scholar
• Colín-LozanoB, Estrada-SotoS, Chávez-SilvaF, et al. Design, synthesis and in combo antidiabetic bioevaluation of multitarget phenylpropanoic acids. Molecules. 2018;23(2):1–16. doi:10.3390/molecules23020340
   Web of Science ®Google Scholar
• QaseemA, BarryMJ, HumphreyLL, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(4):279–290. doi:10.7326/M16-186028055075
   PubMed Web of Science ®Google Scholar
• GarberAJ, AbrahamsonMJ, BarzilayJI, et al. American Association of Clinical Endocrinologists‘ comprehensive diabetes management algorithm 2013 consensus statement – executive summary. Endocr Pract. 2013;19(3):536–557. doi:10.4158/EP13176.CS23816937
   PubMed Web of Science ®Google Scholar
• HusseinZ, WentworthJM, NankervisAJ, ProiettoJ, ColmanPG. Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital. Med J Aust. 2004;181(10):536–539. doi:10.5694/j.1326-5377.2004.tb06441.x15540964
   PubMed Web of Science ®Google Scholar
• FouquerayP, LeverveX, FontaineE, BaquiéM, WollheimC. Imeglimin – a new oral anti-diabetic that targets the three key defects of type 2 diabetes. J Diabetes Metab. 2011;02(4). doi:10.4172/2155-6156.1000126
   Google Scholar
• VuylstekeV, ChastainLM, MagguGA, BrownC. Imeglimin: a potential new multi-target drug for type 2 diabetes. Drugs R D. 2015;15(3):227–232. doi:10.1007/s40268-015-0099-326254210
   PubMedGoogle Scholar
• DetailleD, VialG, BorelA-L, et al. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov. 2016;2(1). doi:10.1038/cddiscovery.2015.72
   PubMed Web of Science ®Google Scholar
• MunhozACM, FrodeTS. Isolated compounds from natural products with potential antidiabetic activity – a systematic review. Curr Diabetes Rev. 2017;14.(1). doi:10.2174/1573399813666170505120621
   Web of Science ®Google Scholar
• LiJ, YuH, WangS, et al. Natural products, an important resource for discovery of <br>multitarget drugs and functional food for regulation of hepatic glucose metabolism. Drug Des Devel Ther. 2018;12:121–135. doi:10.2147/DDDT.S151860
   PubMed Web of Science ®Google Scholar
• MsomiNZ, ShodeFO, PooeOJ, Mazibuko-MbejeS, SimelaneMBC. Iso-mukaadial acetate from warburgia salutaris enhances glucose uptake in the l6 rat myoblast cell line. Biomolecules. 2019;9(10):10. doi:10.3390/biom9100520
   Web of Science ®Google Scholar
• LiuC, ZhangM, HuM, et al. Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides. J Endocrinol. 2013;217(2):185–196. doi:10.1530/JOE-12-050223444389
   PubMed Web of Science ®Google Scholar
• ZhouP, XieW, HeS, et al. Ginsenoside Rb1 as an anti-diabetic agent and its underlying mechanism analysis. Cells. 2019;8(3):204. doi:10.3390/cells8030204
   PubMed Web of Science ®Google Scholar
• OlsonS, EnglishRA, GuentherRS, ClaiborneAB. Facing the reality of drug-resistant tuberculosis in India; 2012 Available from: http://www.ncbi.nlm.nih.gov/books/NBK92617/pdf/TOC.pdf. Accessed 730, 2020.
   Google Scholar
• SpathelfB. Qualitative Structure-Activity Relationships of the Major Tyrocidines, Cyclic Decapeptides from Bacillus Aneurinolyticus. 2013:215.
   Google Scholar
• Méndez-LucioO, NavejaJJ, Vite-CaritinoH, Prieto-MartínezFD, Medina-FrancoJL. One drug for multiple targets: a computational perspective. J Mex Chem Soc. 2016;60(3):168–181. doi:10.29356/jmcs.v60i3.100
   Web of Science ®Google Scholar
• World Health Organization. Malaria chapter 7. World Health Organization technical report series no 936; 2010 Available from: http://www.who.int/ith/ITH_chapter_7.pdf. Accessed 730, 2020.
   Google Scholar
• World malaria report 2018; 2018 Available from: https://www.who.int/malaria/publications/world-malaria-report-2018/en/. Accessed 730, 2020.
   Google Scholar
• ZiningaT, PooeOJ, MakhadoPB, et al. Polymyxin B inhibits the chaperone activity of plasmodium falciparum Hsp70. Cell Stress Chaperones. 2017;22(5):707–715. doi:10.1007/s12192-017-0797-628455613
   PubMed Web of Science ®Google Scholar
• OpokuF, GovenderPP, PooeOJ, SimelaneMBC. Evaluating iso-mukaadial acetate and ursolic acid acetate as plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase inhibitors. Biomolecules. 2019;9(12):861. doi:10.3390/biom9120861
   PubMed Web of Science ®Google Scholar
• McMullanBJ, MostaghimM. Prescribing azithromycin. Aust Prescr. 2015;38(3):87–90. doi:10.18773/austprescr.2015.03026648627
   PubMed Web of Science ®Google Scholar
• NoedlH, KrudsoodS, ChalermratanaK, et al. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis. 2006;43(10):1264–1271. doi:10.1086/50817517051490
   PubMed Web of Science ®Google Scholar
• MillerRS, WongsrichanalaiC, BuathongN, et al. Effective treatment of uncomplicated plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am J Trop Med Hyg. 2006;74(3):401–406. doi:10.4269/ajtmh.2006.74.40116525097
   PubMed Web of Science ®Google Scholar
• MandalS, MandalA, JohanssonHE, OrjaloAV, ParkMH. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc Natl Acad Sci U S A. 2013;110(6):2169–2174. doi:10.1073/pnas.121900211023345430
   PubMed Web of Science ®Google Scholar
• SagorGHM, BerberichT, TakahashiY, NiitsuM, KusanoT. The polyamine spermine protects arabidopsis from heat stress-induced damage by increasing expression of heat shock-related genes. Transgenic Res. 2013;22(3):595–605. doi:10.1007/s11248-012-9666-323080295
   PubMed Web of Science ®Google Scholar
• NjungeJM, MandalP, PrzyborskiJM, BoshoffA, PesceE-R, BlatchGL. PFB0595w is a plasmodium falciparum J protein that co-localizes with PfHsp70-1 and can stimulate its in vitro ATP hydrolysis activity. Int J Biochem Cell Biol. 2015;62:47–53. doi:10.1016/j.biocel.2015.02.00825701168
   PubMed Web of Science ®Google Scholar
• PooeOJ, KöllischG, HeineH, ShonhaiA. Plasmodium falciparum heat shock protein 70 lacks immune modulatory activity. Protein Pept Lett. 2017;24(6):503–510. doi:10.2174/092986652466617021414190928201964
   PubMed Web of Science ®Google Scholar
• PorowińskaD, CzarneckaJ, KomoszyńskiM. Chaperones are necessary for the expression of catalytically active potato apyrases in prokaryotic cells. Appl Biochem Biotechnol. 2014;173(6):1349–1359. doi:10.1007/s12010-014-0858-624801402
   PubMed Web of Science ®Google Scholar
• MurshidA, GongJ, CalderwoodSK. The role of heat shock proteins in antigen cross presentation. Front Immunol. 2012;3:63. doi:10.3389/fimmu.2012.0006322566944
   PubMed Web of Science ®Google Scholar
• ZiningaT, MakumireS, GitauGW, et al. Plasmodium falciparum hop (PfHop) interacts with the Hsp70 chaperone in a nucleotide-dependent fashion and exhibits ligand selectivity. PLoS One. 2015;10(8):e0135326. doi:10.1371/journal.pone.013532626267894
   PubMed Web of Science ®Google Scholar
• MakhobaXH, PooeOJ, MthembuMS. Molecular chaperone assisted expression systems: obtaining pure soluble and active recombinant proteins for structural and therapeutic purposes. J Proteomics Bioinform. 2015;08(09):212–216. doi:10.4172/jpb.1000371
   Google Scholar
• HermayerKL, DakeA. Newer oral and noninsulin therapies to treat type 2 diabetes mellitus. Cleve Clin J Med. 2016;83(5):S18–S26. doi:10.3949/ccjm.83.s1.04
   PubMed Web of Science ®Google Scholar
• HuangJ, OfekG, LaubL, et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature. 2012;491(7424):406–412. doi:10.1038/nature1154423151583
   PubMed Web of Science ®Google Scholar
• PardollDM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi:10.1038/nrc323922437870
   PubMed Web of Science ®Google Scholar
• ProschakE, StarkH, MerkD. Polypharmacology by design: a medicinal chemist’s perspective on multitargeting compounds. J Med Chem. 2019;62(2):420–444. doi:10.1021/acs.jmedchem.8b0076030035545
   PubMed Web of Science ®Google Scholar
• BolognesiML, CavalliA. Multitarget drug discovery and polypharmacology. ChemMedChem. 2016;11(12):1190–1192. doi:10.1002/cmdc.20160016127061625
   PubMed Web of Science ®Google Scholar
• KonecnyGE, PegramMD, VenkatesanN, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66(3):1630–1639. doi:10.1158/0008-5472.CAN-05-118216452222
   PubMed Web of Science ®Google Scholar
• FlinnIW, O’BrienS, KahlB, et al. Duvelisib, a novel oral dual inhibitor of PI3K-d,g, is clinically active in advanced hematologic malignancies. Blood. 2018;131(8):877–887. doi:10.1182/blood-2017-05-78656629191916
   PubMed Web of Science ®Google Scholar
• KucuksayanE, OzbenT. Hybrid compounds as multitarget directed anticancer agents. Curr Top Med Chem. 2016;17(8):907–918. doi:10.2174/1568026616666160927155515
   Web of Science ®Google Scholar
• SharmaA, HillA, KurbatovaE, et al. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study. Lancet Infect Dis. 2017;17(7):707–715. doi:10.1016/S1473-3099(17)30247-528499828
   PubMed Web of Science ®Google Scholar
• WHO. Global Tuberculosis Report 2017. 2017. doi:WHO/HTM/TB/2017.23
   Google Scholar
• SejlitzT, NeujahrHY. Phenol hydroxylase from yeast. Eur J Biochem. 1987;170(1–2):343–349. doi:10.1111/j.1432-1033.1987.tb13705.x3319618
   PubMedGoogle Scholar
• PooranA, PietersonE, DavidsM, TheronG, DhedaK. What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa? PLoS One. 2013;8(1):e54587. doi:10.1371/journal.pone.005458723349933
   PubMed Web of Science ®Google Scholar
• AbedinzadehM, GaeiniM, SardariS. Natural antimicrobial peptides against mycobacterium tuberculosis. J Antimicrob Chemother. 2014;70(5):1285–1289. doi:10.1093/jac/dku570
   Web of Science ®Google Scholar
• VelayatiAA, FarniaP, MasjediMR, et al. Totally drug-resistant tuberculosis strains: evidence of adaptation at the cellular level. Eur Respir J. 2009;34(5):1202–1203. doi:10.1183/09031936.0008190919880622
   PubMed Web of Science ®Google Scholar
• GuptaVK, KumarMM, BishtD, KaushikA. Plants in our combating strategies against mycobacterium tuberculosis: progress made and obstacles met. Pharm Biol. 2017;55(1):1536–1544. doi:10.1080/13880209.2017.130944028385088
   PubMed Web of Science ®Google Scholar
• LaiMJ, LiuCC, JiangSJ, et al. Antimycobacterial activities of endolysins derived from a mycobacteriophage, BTCU-1. Molecules. 2015;20(10):19277–19290. doi:10.3390/molecules20101927726506338
   PubMed Web of Science ®Google Scholar
• AyeniG, OJ PooeP, M SinghS, N NundkumarN, MBC SimelaneS. Cytotoxic and antioxidant activities of selected south african medicinal plants. Pharmacogn J. 2019;11(6):1532–1539. doi:10.5530/pj.2019.11.234
   Google Scholar
• HatherleyR, BrownDK, MusyokaTM, et al. SANCDB: a South African natural compound database. J Cheminform. 2015;7(1):1–9. doi:10.1186/s13321-015-0080-825705261
   PubMed Web of Science ®Google Scholar
• LakshmananD, WerngrenJ, JoseL, et al. Ethyl p-methoxycinnamate isolated from a traditional anti-tuberculosis medicinal herb inhibits drug resistant strains of mycobacterium tuberculosis in vitro. Fitoterapia. 2011;82(5):757–761. doi:10.1016/j.fitote.2011.03.00621459133
   PubMed Web of Science ®Google Scholar
• LawalTO, AdeniyiBA, AdegokeAO, FranzblauSG, MahadyGB. In vitro susceptibility of mycobacterium tuberculosis to extracts of eucalyptus camaldulensis and eucalyptus torelliana and isolated compounds. Pharm Biol. 2012;50(1):92–98. doi:10.3109/13880209.2011.62595322129202
   PubMed Web of Science ®Google Scholar
• ThakurJP, GothwalPP. Edible plants as a source of antitubercular agents. J Pharmacogn Phytochem. 2015;4(1):228–234.
   Google Scholar
• TekaleS, MasheleS, PooeO, ThoreS Biological role of chalcones in medicinal chemistry. IntechOpen; 2020 Available from: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=2ahUKEwigvouT_43oAhWLSxUIHX-QCh8QFjABegQIAxAB&url=https%3A%2F%2Fcdn.intechopen.com%2Fpdfs%2F71321.pdf&usg=AOvVaw2K2uNmFU9MwJYDpvBkF13V. Accessed 730, 2020.
   Google Scholar
• Molina-SalinasGM, Uc-CachónAH, Peña-RodríguezLM, Dzul-BehADJ, Graća-MedranoRME. Bactericidal effect of the leaf extract from musa spp. (AAB group, silk subgroup), cv. “manzano” against multidrug-resistant mycobacterium tuberculosis. J Med Food. 2019;22(11):1183–1185. doi:10.1089/jmf.2019.007531268391
   PubMed Web of Science ®Google Scholar
• MulthoffG. Activation of natural killer cells by heat shock protein 70. Int J Hyperthermia. 2002;18(6):576–585. doi:10.1080/0265673021000017109.12537756
   PubMed Web of Science ®Google Scholar
• LiK, Schurig-BriccioLA, FengX, et al. Multitarget drug discovery for tuberculosis and other infectious diseases. J Med Chem. 2014;57(7):3126–3129. doi:10.1021/jm500131s24568559
   PubMed Web of Science ®Google Scholar
• MakobongoMO, EinckL, PeekRM, MerrellDS. In vitro characterization of the anti-bacterial activity of SQ109 against helicobacter pylori. PLoS One. 2013;8(7):1–16. doi:10.1371/journal.pone.0068917
   Web of Science ®Google Scholar
• HeinrichN, DawsonR, BoisJ, et al. Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients. J Antimicrob Chemother. 2014;70(5):1558–1566. doi:10.1093/jac/dku553
   Web of Science ®Google Scholar
• TB Alliance. Pretomanid and BPaL regimen for treatment of highly-resistant tuberculosis. Oral Presentation. 2019. doi:10.1017/CBO9781107415324.004
   Google Scholar
• WellingtonS, HungDT. The expanding diversity of mycobacterium tuberculosis drug targets. ACS Infect Dis. 2018;4(5):696–714. doi:10.1021/acsinfecdis.7b0025529412643
   PubMed Web of Science ®Google Scholar
• TangJ, WangB, WuT, et al. Design, synthesis, and biological evaluation of pyrazolo[1,5-a]pyridine-3-carboxamides as novel antitubercular agents. ACS Med Chem Lett. 2015;6(7):814–818. doi:10.1021/acsmedchemlett.5b0017626191372
   PubMed Web of Science ®Google Scholar
• LiuY, GaoY, LiuJ, et al. The compound TB47 is highly bactericidal against mycobacterium ulcerans in a buruli ulcer mouse model. Nat Commun. 2019;10(1):1–9. doi:10.1038/s41467-019-08464-y30602773
   PubMed Web of Science ®Google Scholar
• NjireM, WangN, WangB, et al. Pyrazinoic acid inhibits a bifunctional enzyme in mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017;61(7):1–15. doi:10.1128/AAC.00070-17
   Web of Science ®Google Scholar
• LiuP, YangY, TangY, et al. Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents. Eur J Med Chem. 2019;163:169–182. doi:10.1016/j.ejmech.2018.11.05430508666
   PubMed Web of Science ®Google Scholar
• SchmelcherM, DonovanDM, LoessnerMJ. Bacteriophage endolysins as novel antimicrobials. Future Microbiol. 2012;7(10):1147–1171. doi:10.2217/fmb.12.9723030422
   PubMed Web of Science ®Google Scholar
• HatfullGF. The Secret Lives of Mycobacteriophages. Vol. 82 1st ed. Elsevier Inc.; 2012. doi:10.1016/B978-0-12-394621-8.00015-7
   Google Scholar
• HaqIU, ChaudhryWN, AkhtarMN, AndleebS, QadriI. Bacteriophages and their implications on future biotechnology: a review. Virol J. 2012;9(1):9. doi:10.1186/1743-422X-9-922234269
   PubMed Web of Science ®Google Scholar
• PirnayJP, VerbekenG, CeyssensPJ, et al. The magistral phage. Viruses. 2018;10(2):1–7. doi:10.3390/v10020064
   Web of Science ®Google Scholar
• SchuchR, LeeHM, SchneiderBC, et al. Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant staphylococcus aureus-induced murine bacteremia. J Infect Dis. 2014;209(9):1469–1478. doi:10.1093/infdis/jit63724286983
   PubMed Web of Science ®Google Scholar
• ThummeepakR, KittiT, KunthalertD, SitthisakS. Enhanced antibacterial activity of acinetobacter baumannii bacteriophage ØABP-01 endolysin (LysABP-01) in combination with colistin. Front Microbiol. 2016;7(SEP):1–8. doi:10.3389/fmicb.2016.0140226834723
   PubMed Web of Science ®Google Scholar
• SchuchR, KhanBK, RazA, RotoloJA, WittekindM. Bacteriophage lysin CF-301, a potent antistaphylococcal biofilm agent. Antimicrob Agents Chemother. 2017;61(7):1–18. doi:10.1128/AAC.02666-16
   Web of Science ®Google Scholar
• LoveM, BhandariD, DobsonR, BillingtonC. Potential for bacteriophage endolysins to supplement or replace antibiotics in food production and clinical care. Antibiotics. 2018;7(1):17. doi:10.3390/antibiotics7010017
   Web of Science ®Google Scholar
• Rodríguez-RubioL, GutiérrezD, DonovanDM, MartínezB, RodríguezA, GarcíaP. Phage lytic proteins: biotechnological applications beyond clinical antimicrobials. Crit Rev Biotechnol. 2015;8551(November):1–11. doi:10.3109/07388551.2014.993587
   Web of Science ®Google Scholar
• HerpersB. Endolysins: finding the answers to the problem of antibiotic resistance. Biomed Sci. 2015;(October):560–562.
   Google Scholar
• LiQ, ZhouM, FanX, YanJ, LiW, XieJ. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against mycobacterium via altering the cell wall permeability. Sci Rep. 2016;6(March):1–14. doi:10.1038/srep2870128442746
   PubMed Web of Science ®Google Scholar
• DedrickRM, Guerrero-bustamanteCA, GarlenaRA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant mycobacterium abscessus. Nat Med. 2019;25(May):730–733. doi:10.1038/s41591-019-0437-z31068712
   PubMed Web of Science ®Google Scholar
• GondilVS, ChhibberS. Exploring potential of phage therapy for tuberculosis using model organism. Biomed Biotechnol Res J. 2018;9–15. doi:10.4103/bbrj.bbrj
   Google Scholar
• KalraS, KalraB, AgrawalN, UnnikrishnanA. Understanding diabetes in patients with HIV/AIDS. Diabetol Metab Syndr. 2011;3(1):1–7. doi:10.1186/1758-5996-3-221226946
   PubMed Web of Science ®Google Scholar
• SamadF, HarrisM, PuskasCM, et al. Incidence of diabetes mellitus and factors associated with its development in HIV-positive patients over the age of 50. BMJ Open Diabetes Res Care. 2017;5(1):1–10. doi:10.1136/bmjdrc-2017-000457
   Web of Science ®Google Scholar
• ViaynaE, SolaI, Di PietroO, Munoz-TorreroD. Human disease and drug pharmacology, complex as real life. Curr Med Chem. 2013;20(13):1623–1634. doi:10.2174/092986731132013000223410162
   PubMed Web of Science ®Google Scholar
• ShawJE, SicreeRA, ZimmetPZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14. doi:10.1016/j.diabres.2009.10.00719896746
   PubMed Web of Science ®Google Scholar
• TargetG, FactsF. Global NCD Target Reduce Premature. 2020.
   Google Scholar
• CefaloCMA, CintiF, MoffaS, et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019;18(1):1–14. doi:10.1186/s12933-019-0828-y30626440
   PubMed Web of Science ®Google Scholar
• EganA, VellaA. TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes. Expert Opin Investig Drugs. 2019;28(9):741–747. doi:10.1080/13543784.2019.1654993
   PubMed Web of Science ®Google Scholar
• McCallAL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin North Am. 2012;41(1):57–87. doi:10.1016/j.ecl.2012.03.00122575407
   PubMed Web of Science ®Google Scholar
• YuX, YeL, ZhangH, et al. Ginsenoside rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice. J Ginseng Res. 2015;39(3):199–205. doi:10.1016/j.jgr.2014.11.00426199550
   PubMed Web of Science ®Google Scholar
• MabhidaSE, JohnsonR, NdlovuM, LouwJ, OpokuA, MosaRA. Molecular basis of the anti-hyperglycemic activity of RA-3 in hyperlipidemic and streptozotocin-induced type 2 diabetes in rats. Diabetol Metab Syndr. 2019;11(1):1–5. doi:10.1186/s13098-019-0424-z30622652
   PubMed Web of Science ®Google Scholar
• MabhidaSE, MosaRA, PendukaD, et al. A lanosteryl triterpene from protorhus longifolia improves glucose tolerance and pancreatic beta cell ultrastructure in type 2 diabetic rats. Molecules. 2017;22(8):1–11. doi:10.3390/molecules22081252
   Web of Science ®Google Scholar
• MosaRA, CeleND, MabhidaSE, ShabalalaSC, PendukaD, OpokuAR. In vivo antihyperglycemic activity of a lanosteryl triterpene from Protorhus longifolia. Molecules. 2015;20(7):13374–13383. doi:10.3390/molecules20071337426205060
   PubMed Web of Science ®Google Scholar
• MachabaKE, CobongelaSZZ, MosaRA, OladipupoLA, DjarovaTG, OpokuAR. In vivo anti-hyperlipidemic activity of the triterpene from the stem bark of protorhus longifolia (Benrh) engl. Lipids Health Dis. 2014;13(1):1–7. doi:10.1186/1476-511X-13-13124382338
   PubMed Web of Science ®Google Scholar
• SellamuthuPS, ArulselvanP, KamalrajS, FakuraziS, KandasamyM. Protective nature of mangiferin on oxidative stress and antioxidant status in tissues of streptozotocin-induced diabetic rats. ISRN Pharmacol. 2013;2013:1–10. doi:10.1155/2013/750109
   Google Scholar
• MinQ, CaiX, SunW, et al. Identification of mangiferin as a potential glucokinase activator by structure-based virtual ligand screening. Sci Rep. 2017;7(November 2016):2–10. doi:10.1038/srep4468128127053
   PubMed Web of Science ®Google Scholar
• BolognesiM. Polypharmacology in a single drug: multitarget drugs. Curr Med Chem. 2013;20(13):1639–1645. doi:10.2174/092986731132013000423410164
   PubMed Web of Science ®Google Scholar
• Agis-TorresA, SollhuberM, FernandezM, Sanchez-MonteroJM. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for alzheimer’s disease. Curr Neuropharmacol. 2014;12(1):2–36. doi:10.2174/1570159x11311666004724533013
   PubMed Web of Science ®Google Scholar
• GeldenhuysW, Van der SchyfC. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem. 2013;20(13):1662–1672. doi:10.2174/0929867311320999011223410161
   PubMed Web of Science ®Google Scholar
• ViegasC, BolzaniVS, PimentelLSB, et al. New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids. Bioorg Med Chem. 2005;13(13):4184–4190. doi:10.1016/j.bmc.2005.04.03015878668
   PubMed Web of Science ®Google Scholar
• MorphyR, KayC, RankovicZ. From magic bullets to designed multiple ligands. Drug Discov Today. 2004;9(15):641–651. doi:10.1016/S1359-6446(04)03163-015279847
   PubMed Web of Science ®Google Scholar
• MorphyR, RankovicZ. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48(21):6523–6543. doi:10.1021/jm058225d16220969
   PubMed Web of Science ®Google Scholar
• WertheimerA. The economics of polypharmacology: fixed dose combinations and drug cocktails. Curr Med Chem. 2013;20(13):1635–1638. doi:10.2174/092986731132013000323410163
   PubMed Web of Science ®Google Scholar
• DiasKST, De PaulaCT, RiquielMM, et al. Recent applications of the multi-target directed ligands approach for the treatment of alzheimer’s disease. Rev Virtual De Quimica. 2015;7(2):609–648. doi:10.5935/1984-6835.20150027
   Google Scholar
• Manssour FragaC, BarreiroE. New insights for multifactorial disease therapy: the challenge of the symbiotic drugs. Curr Drug Ther. 2008;3(1):1–13. doi:10.2174/157488508783331225
   Google Scholar
• LinHH, ZhangL, YanR, LuJJ, HuY. Network analysis of drug-target interactions: a study on FDA-approved new molecular entities between 2000 to 2015. Sci Rep. 2017;7(1). doi:10.1038/s41598-017-12061-8
   Web of Science ®Google Scholar
• LansburyPT. Back to the future: the ’old-fashioned’ way to new medications for neurodegeneration. Nat Rev Neurosci. 2004;10(7):S51. doi:10.1038/nrn1435
   Web of Science ®Google Scholar
• CavalliA, BolognesiML, MinariniA, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51(3):347–372. doi:10.1021/jm700936418181565
   PubMed Web of Science ®Google Scholar
• BajicV, MilovanovicE, Spremo-PotparevicB, et al. Treatment of alzheimer’s disease: classical therapeutic approach. Curr Pharm Anal. 2016;12(2):82–90. doi:10.2174/1573412911666150611184740
   Web of Science ®Google Scholar
• ViegasFPD, SimõesMCR, Da RochaMD, CastelliMR, MoreiraMS, JuniorCV. Alzheimer’s disease: characterization, evolution and implications of the neuroinflammatory process. Rev Virtual De Quimica. 2011;3(4):286–306. doi:10.5935/1984-6835.20110034
   Google Scholar
• Divino da RochaM, Pereira Dias ViegasF, Cristina CamposH, et al. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders ii: alzheimers disease. CNS Neurol Disord Drug Targets. 2011;10(2):251–270. doi:10.2174/18715271179448042920874701
   PubMed Web of Science ®Google Scholar
• Munoz-TorreroD. Editorial (hot topic: complexity against complexity: multitarget drugs). Curr Med Chem. 2013;20(13):1621–1622. doi:10.2174/092986731132013000123458613
   PubMed Web of Science ®Google Scholar
• YoudimMBH, BuccafuscoJJ. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci. 2005;26(1):27–35. doi:10.1016/j.tips.2004.11.00715629202
   PubMed Web of Science ®Google Scholar
• CarreirasM, MendesE, PerryM, FranciscoA, Marco-ContellesJ. The multifactorial nature of alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem. 2013;13(15):1745–1770. doi:10.2174/1568026611313999013523931435
   PubMed Web of Science ®Google Scholar
• CsermelyP, ÁgostonV, PongorS. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol Sci. 2005;26(4):178–182. doi:10.1016/j.tips.2005.02.00715808341
   PubMed Web of Science ®Google Scholar
• GiuliaN, SimonaS, MariaD, SimonaR. Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in alzheimer’s disease. Curr Top Med Chem. 2017;17(27). doi:10.2174/1568026617666170607114232
   Web of Science ®Google Scholar
• WangT, LiuX, GuanJ, et al. Advancement of multi-target drug discoveries and promising applications in the field of alzheimer’s disease. Eur J Med Chem. 2019;169:200–223. doi:10.1016/j.ejmech.2019.02.07630884327
   PubMed Web of Science ®Google Scholar
• ZhanP, LiuX. Rationally designed multitarget anti-HIV agents. Curr Med Chem. 2013;20(13):1743–1758. doi:10.2174/092986731132013001123410170
   PubMed Web of Science ®Google Scholar
• Rodrigues SimoesM, Dias ViegasF, MoreiraM, et al. Donepezil: an important prototype to the design of new drug candidates for alzheimer’s disease. Mini Rev Med Chem. 2014;14(1):2–19. doi:10.2174/138955751366613111920135324251806
   PubMed Web of Science ®Google Scholar
• LeónR, GarciaAG, Marco-ContellesJ. Recent advances in the multitarget-directed ligands approach for the treatment of alzheimer’s disease. Med Res Rev. 2013;33(1):139–189. doi:10.1002/med.2024821793014
   PubMed Web of Science ®Google Scholar
• CunyGD. Neurodegenerative diseases: challenges and opportunities. Future Med Chem. 2012;4(13):1647–1649. doi:10.4155/fmc.12.12322924500
   PubMed Web of Science ®Google Scholar
• Simone Tranches DiasK, ViegasC. Multi-target directed drugs: a modern approach for design of new drugs for the treatment of alzheimer’s disease. Curr Neuropharmacol. 2014;12(3):239–255. doi:10.2174/1570159x120314051115320024851088
   PubMed Web of Science ®Google Scholar
• CrewsL, MasliahE. Molecular mechanisms of neurodegeneration in alzheimer’s disease. Hum Mol Genet. 2010;19(R1):R12–R20. doi:10.1093/hmg/ddq16020413653
   PubMed Web of Science ®Google Scholar
• KumarK, KumarA, KeeganRM, DeshmukhR. Recent advances in the neurobiology and neuropharmacology of alzheimer’s disease. Biomed Pharmacother. 2018;98:297–307. doi:10.1016/j.biopha.2017.12.05329274586
   PubMed Web of Science ®Google Scholar
• ShiS, WangZ, QiaoZ. The multifunctional anti-inflammatory drugs used in the therapy of alzheimer’s disease. Curr Med Chem. 2013;20(20):2583–2588. doi:10.2174/092986731132020000623590711
   PubMed Web of Science ®Google Scholar
• DivariS, ValettiF, CaposioP, et al. The oxygenase component of phenol hydroxylase from acinetobacter radioresistens S13. Eur J Biochem. 2003;270(10):2244–2253. doi:10.1046/j.1432-1033.2003.03592.x12752444
   PubMedGoogle Scholar
• NolanLC, O’ConnorKE. Dioxygenase- and monooxygenase-catalysed synthesis of cis-dihydrodiols, catechols, epoxides and other oxygenated products. Biotechnol Lett. 2008;30(11):1879–1891. doi:10.1007/s10529-008-9791-518612597
   PubMed Web of Science ®Google Scholar