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Volume 21, Issue 14
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Introduction

Chagas disease is a neglected disease caused by the protozoan that affects 7 million people worldwide. The current treatment is limited due to safety and efficacy issues. Therefore, the search for new antiparasitic drugs is fundamental. The enzyme squalene synthase (SQS) is an attractive therapeutic target since it participates in the ergosterol biosynthesis pathway.

Objective

In the present study, we explored the Brazilian biodiversity to search for potential inhibitors of SQS (SQS) using ligand and structure-based virtual screening strategies.

Materials and Methods

A virtual screening was performed within the NuBBE database, with more than 2,200 natural products (NP) or semisynthetic derivatives from the Brazilian biodiversity. Molecular docking and ADMET predictions were then performed.

Results

A set of 12 NP showed interactions with SQS like those observed by known inhibitors and shared literature evidence that supports the predicted activity.

Conclusion

Three compounds (flavonoids) showed good ADMET properties as potential inhibitors of SQS.

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2024-11-19

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References

  1. The causes and impacts of neglected tropical and zoonotic diseases: Opportunities for integrated intervention strategies. National Academies Press (US): Washington (DC)2022
     [Google Scholar]
  2. World Health Organization. Neglected tropical diseases,Available From: https://www.who.int/health-topics/neglected-tropical-diseases#tab=tab_2 (Accessed on Sep 12 2022)
  3. GachelinG. BestettiR.B. Early clinics of the cardiac forms of Chagas’ disease: Discovery and study of original medical files (1909–1915).Int. J. Cardiol.201724420621210.1016/j.ijcard.2017.06.102 28676242
     [Google Scholar]
  4. World Health Organization.Available From: https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)(Accessed on Sep 12 2022).
  5. ConnersE.E. VinetzJ.M. WeeksJ.R. BrouwerK.C. A global systematic review of Chagas disease prevalence among migrants.Acta Trop.2016156687810.1016/j.actatropica.2016.01.002 26777312
     [Google Scholar]
  6. LidaniK.C.F. AndradeF.A. BaviaL. DamascenoF.S. BeltrameM.H. Messias-ReasonI.J. SandriT.L. Chagas disease: From discovery to a worldwide health problem.Front. Public Health2019716610.3389/fpubh.2019.00166 31312626
     [Google Scholar]
  7. Pan American Health Organization. Chagas disease,Available From: https://www.paho.org/en/topics/chagas-disease( Accessed on Sep 12 2022).
  8. Pérez-MolinaJ.A. MolinaI. Chagas disease.Lancet201839110115829410.1016/S0140‑6736(17)31612‑4 28673423
     [Google Scholar]
  9. Rangel-GamboaL. López-GarcíaL. Moreno-SánchezF. Hoyo-UlloaI. Vega-MémijeM.E. Mendoza-BazánN. Romero-ValdovinosM. Olivo-DíazA. VillalobosG. Martínez-HernándezF. Trypanosoma cruzi infection associated with atypical clinical manifestation during the acute phase of the Chagas disease.Parasit. Vectors201912150610.1186/s13071‑019‑3766‑3 31666114
     [Google Scholar]
  10. MatsudaN.M. MillerS.M. EvoraP.R.B. The chronic gastrointestinal manifestations of Chagas disease.Clinics200964121219122410.1590/S1807‑59322009001200013 20037711
     [Google Scholar]
  11. GuarnerJ. Chagas disease as example of a reemerging parasite.Semin. Diagn. Pathol.201936316416910.1053/j.semdp.2019.04.008 31006555
     [Google Scholar]
  12. DaréL.O. BruandP.E. GérardD. MarinB. LameyreV. BoumédièneF. PreuxP.M. Co-morbidities of mental disorders and chronic physical diseases in developing and emerging countries: A meta-analysis.BMC Public Health201919130410.1186/s12889‑019‑6623‑6 30866883
     [Google Scholar]
  13. OPS OP of health. control, interruption of transmission and elimination of chagas disease as a public health problem. evaluation, verification and validation guide.Washington, DCOrganización Panamericana de LaSalud2019
     [Google Scholar]
  14. ScarimC.B. JornadaD.H. ChelucciR.C. de AlmeidaL. dos SantosJ.L. ChungM.C. Current advances in drug discovery for Chagas disease.Eur. J. Med. Chem.201815582483810.1016/j.ejmech.2018.06.040 30033393
     [Google Scholar]
  15. KratzJ.M. Drug discovery for chagas disease: A viewpoint.Acta Trop.201919810510710.1016/j.actatropica.2019.105107 31351074
     [Google Scholar]
  16. JacksonY. WyssaB. ChappuisF. Tolerance to nifurtimox and benznidazole in adult patients with chronic Chagas’ disease.J. Antimicrob. Chemother.202075369069610.1093/jac/dkz473 31754690
     [Google Scholar]
  17. PattersonS. WyllieS. Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects.Trends Parasitol.201430628929810.1016/j.pt.2014.04.003 24776300
     [Google Scholar]
  18. CamposM.C. PhelanJ. FranciscoA.F. TaylorM.C. LewisM.D. PainA. ClarkT.G. KellyJ.M. Genome-wide mutagenesis and multi-drug resistance in American trypanosomes induced by the front-line drug benznidazole.Sci. Rep.2017711440710.1038/s41598‑017‑14986‑6 29089615
     [Google Scholar]
  19. RevolloS. OuryB. VelaA. TibayrencM. SerenoD. In vitro benznidazole and nifurtimox susceptibility profile of trypanosoma cruzi strains belonging to discrete typing units tci, tcii, and tcv.Pathogens20198419710.3390/pathogens8040197 31635071
     [Google Scholar]
  20. RabeloV.W.H. RomeiroN.C. AbreuP.A. Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.J. Steroid Biochem. Mol. Biol.201717130531710.1016/j.jsbmb.2017.05.002 28479228
     [Google Scholar]
  21. Osorio-MéndezJ.F. CevallosA.M. Discovery and genetic validation of chemotherapeutic targets for chagas’ disease.Front. Cell. Infect. Microbiol.2019843910.3389/fcimb.2018.00439 30666299
     [Google Scholar]
  22. VillaltaF. RachakondaG. Advances in preclinical approaches to Chagas disease drug discovery.Expert Opin. Drug Discov.201914111161117410.1080/17460441.2019.1652593 31411084
     [Google Scholar]
  23. de SouzaW. RodriguesJ.C.F. Sterol biosynthesis pathway as target for anti-trypanosomatid drugs.Interdiscip. Perspect. Infect. Dis.2009200911910.1155/2009/642502 19680554
     [Google Scholar]
  24. UrbinaJ.A. Ergosterol biosynthesis and drug development for Chagas disease.Mem. Inst. Oswaldo Cruz2009104Suppl. 131131810.1590/S0074‑02762009000900041 19753490
     [Google Scholar]
  25. ShangN. LiQ. KoT.P. ChanH.C. LiJ. ZhengY. HuangC.H. RenF. ChenC.C. ZhuZ. GalizziM. LiZ.H. Rodrigues-PovedaC.A. Gonzalez-PacanowskaD. Veiga-SantosP. de CarvalhoT.M.U. de SouzaW. UrbinaJ.A. WangA.H.J. DocampoR. LiK. LiuY.L. OldfieldE. GuoR.T. Squalene synthase as a target for Chagas disease therapeutics.PLoS Pathog.2014105e100411410.1371/journal.ppat.1004114 24789335
     [Google Scholar]
  26. GoldsteinJ.L. BrownM.S. The cholesterol quartet.200129255201310131210.1126/science.1061815
     [Google Scholar]
  27. UrbinaJ.A. ConcepcionJ.L. RangelS. VisbalG. LiraR. Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana.Mol. Biochem. Parasitol.20021251-2354510.1016/S0166‑6851(02)00206‑2 12467972
     [Google Scholar]
  28. BenaimG. SandersJ.M. Garcia-MarchánY. ColinaC. LiraR. CalderaA.R. PayaresG. SanojaC. BurgosJ.M. Leon-RossellA. ConcepcionJ.L. SchijmanA.G. LevinM. OldfieldE. UrbinaJ.A. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.J. Med. Chem.200649389289910.1021/jm050691f 16451055
     [Google Scholar]
  29. UrbinaJ.A. ConcepcionJ.L. MontalvettiA. RodriguezJ.B. DocampoR. Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas’ disease.Antimicrob. Agents Chemother.20034762047205010.1128/AAC.47.6.2047‑2050.2003 12760897
     [Google Scholar]
  30. UrbinaJ.A. ConcepcionJ.L. CalderaA. PayaresG. SanojaC. OtomoT. HiyoshiH. In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi.Antimicrob. Agents Chemother.20044872379238710.1128/AAC.48.7.2379‑2387.2004 15215084
     [Google Scholar]
  31. IzumiE. Ueda-NakamuraT. Dias FilhoB.P. Veiga JúniorV.F. NakamuraC.V. Natural products and Chagas’ disease: A review of plant compounds studied for activity against Trypanosoma cruzi.Nat. Prod. Rep.201128480982310.1039/c0np00069h 21290079
     [Google Scholar]
  32. AlvianoD.S. BarretoA.L.S. DiasF.A. RodriguesI.A. RosaM.S.S. AlvianoC.S. SoaresR.M.A. Conventional therapy and promising plant-derived compounds against trypanosomatid parasites.Front. Microbiol.2012328310.3389/fmicb.2012.00283 22888328
     [Google Scholar]
  33. Moraes NetoR.N. SetúbalR.F.B. HiginoT.M.M. Brelaz-de-CastroM.C.A. da SilvaL.C.N. AliançaA.S.S. Aliança AS dos S. Asteraceae plants as sources of compounds against leishmaniasis and chagas disease.Front. Pharmacol.20191047710.3389/fphar.2019.00477 31156427
     [Google Scholar]
  34. ShahhamzeheiN. AbdelfatahS. EfferthT. In silico and in vitro identification of pan-coronaviral main protease inhibitors from a large natural product library.Pharmaceuticals202215330810.3390/ph15030308 35337106
     [Google Scholar]
  35. Sama-aeI. SangkanuS. SiyadatpanahA. NorouziR. ChupromJ. MitsuwanW. SurinkaewS. BoonhokR. PaulA.K. MahboobT. Targeting acanthamoeba proteins interaction with flavonoids of propolis extract by in vitro and in silico studies for promising therapeutic effects.F1000 Res.202311127410.12688/f1000research.126227.3
     [Google Scholar]
  36. ValliM. RussoH.M. BolzaniV.S. The potential contribution of the natural products from Brazilian biodiversity to bioeconomy.An. Acad. Bras. Cienc.201890Suppl. 176377810.1590/0001‑3765201820170653 29668803
     [Google Scholar]
  37. PilonA.C. ValliM. DamettoA.C. PintoM.E.F. FreireR.T. Castro-GamboaI. AndricopuloA.D. BolzaniV.S. NuBBEDB: an updated database to uncover chemical and biological information from Brazilian biodiversity.Sci. Rep.201771721510.1038/s41598‑017‑07451‑x 28775335
     [Google Scholar]
  38. Saldívar-GonzálezF.I. ValliM. AndricopuloA.D. da Silva BolzaniV. Medina-FrancoJ.L. Chemical space and diversity of the nubbe database: a chemoinformatic characterization.J. Chem. Inf. Model.2019591748510.1021/acs.jcim.8b00619 30508485
     [Google Scholar]
  39. O’BoyleN.M. BanckM. JamesC.A. MorleyC. VandermeerschT. HutchisonG.R. Open Babel: An open chemical toolbox.J. Cheminform.2011313310.1186/1758‑2946‑3‑33 21982300
     [Google Scholar]
  40. SunseriJ. KoesD.R. Pharmit: Interactive exploration of chemical space.Nucleic Acids Res.201644W1W442W44810.1093/nar/gkw287 27095195
     [Google Scholar]
  41. KoesD.R. CamachoC.J. Pharmer: Efficient and exact pharmacophore search.J. Chem. Inf. Model.20115161307131410.1021/ci200097m 21604800
     [Google Scholar]
  42. LagorceD. BouslamaL. BecotJ. MitevaM.A. VilloutreixB.O. FAF-Drugs4: Free ADME-tox filtering computations for chemical biology and early stages drug discovery.Bioinformatics201733223658366010.1093/bioinformatics/btx491 28961788
     [Google Scholar]
  43. TrottO. OlsonA.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.2009312NA10.1002/jcc.21334 19499576
     [Google Scholar]
  44. DallakyanS. OlsonA. Small-molecule library screening by docking with pyrx.Methods in Molecular Biology.New York, NYHumana Press2015243250
     [Google Scholar]
  45. GuexN. PeitschM.C. SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling.Electrophoresis199718152714272310.1002/elps.1150181505 9504803
     [Google Scholar]
  46. BIOVIA. Discovery studio visualizer.Dassault Systèmes BIOVIA2017
     [Google Scholar]
  47. PiresD.E.V. BlundellT.L. AscherD.B. PkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures.J. Med. Chem.20155894066407210.1021/acs.jmedchem.5b00104 25860834
     [Google Scholar]
  48. LiF ZhangL ZhangZ Lie group machine learning.201810.1515/9783110499506
     [Google Scholar]
  49. GoadL. KeithlyJ. BermanJ. BeachD. HolzG. Possible implications for chemotherapy.Leishmania: The Sterols of Leishmania Promastigotes and Amastigotes.Boston, MASpringer US198949550110.1007/978‑1‑4613‑1575‑9_61
     [Google Scholar]
  50. TasdemirD. KaiserM. BrunR. YardleyV. SchmidtT.J. TosunF. RüediP. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: In vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies.Antimicrob. Agents Chemother.20065041352136410.1128/AAC.50.4.1352‑1364.2006 16569852
     [Google Scholar]
  51. LeiteA.C. Placeres NetoA. AmbrozinA.R.P. FernandesJ.B. VieiraP.C. Silva MF das GF da, de Albuquerque S. Trypanocidal activity of flavonoids and limonoids isolated from myrsinaceae and meliaceae active plant extracts.Rev. Bras. Farmacogn.201020116
     [Google Scholar]
  52. GreccoS.S. ReimãoJ.Q. TemponeA.G. SartorelliP. CunhaR.L.O.R. RomoffP. FerreiraM.J.P. FáveroO.A. LagoJ.H.G. In vitro antileishmanial and antitrypanosomal activities of flavanones from Baccharis retusa DC. (Asteraceae).Exp. Parasitol.2012130214114510.1016/j.exppara.2011.11.002 22143090
     [Google Scholar]
  53. HuberL Rodrigues-AmayaD. Flavonoids and flavones: The brazilian sources and factors that influence the composition in food.Brazilian J. Food Nutr.2008191
     [Google Scholar]
  54. Mamani-MatsudaM. RambertJ. MalvyD. Lejoly-BoisseauH. DaulouèdeS. ThiolatD. CovesS. CourtoisP. VincendeauP. MossalayiM.D. Quercetin induces apoptosis of trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages.Antimicrob. Agents Chemother.200448392492910.1128/AAC.48.3.924‑929.2004 14982785
     [Google Scholar]
  55. SenG. MukhopadhyayS. RayM. BiswasT. Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity.J. Antimicrob. Chemother.20086151066107510.1093/jac/dkn053 18285311
     [Google Scholar]
  56. LooV.G. LalondeR.G. Role of iron in intracellular growth of Trypanosoma cruzi.Infect. Immun.198445372673010.1128/iai.45.3.726‑730.1984 6381312
     [Google Scholar]
  57. MartinsR.C.C. LagoJ.H.G. AlbuquerqueS. KatoM.J. Trypanocidal tetrahydrofuran lignans from inflorescences of Piper solmsianum.Phytochemistry200364266767010.1016/S0031‑9422(03)00356‑X 12943793
     [Google Scholar]
  58. PiccirilloE. AmaralA. Busca virtual de compostos bioativos: Conceitos e aplicações.Quim. Nova201841666267710.21577/0100‑4042.20170210
     [Google Scholar]
  59. CaronG. DigiesiV. SolaroS. ErmondiG. Flexibility in early drug discovery: Focus on the beyond-Rule-of-5 chemical space.Drug Discov. Today202025462162710.1016/j.drudis.2020.01.012 31991117
     [Google Scholar]
  60. DoakB.C. OverB. GiordanettoF. KihlbergJ. Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates.Chem. Biol.20142191115114210.1016/j.chembiol.2014.08.013 25237858
     [Google Scholar]
  61. DoakB.C. ZhengJ. DobritzschD. KihlbergJ. How beyond rule of 5 drugs and clinical candidates bind to their targets.J. Med. Chem.20165962312232710.1021/acs.jmedchem.5b01286 26457449
     [Google Scholar]
  62. DoakB.C. KihlbergJ. Drug discovery beyond the rule of 5: Opportunities and challenges.Expert Opin. Drug Discov.201712211511910.1080/17460441.2017.1264385 27883294
     [Google Scholar]
  63. PoongavanamV. DoakB.C. KihlbergJ. Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space.Curr. Opin. Chem. Biol.201844232910.1016/j.cbpa.2018.05.010 29803972
     [Google Scholar]
  64. LipinskiC.A. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.Adv. Drug Deliv. Rev.2016101344110.1016/j.addr.2016.04.029 27154268
     [Google Scholar]
  65. RabeloV.W.H. ViegasD.J. TucciE.M.N. RomeiroN.C. AbreuP.A. Virtual screening and drug repositioning as strategies for the discovery of new antifungal inhibitors of oxidosqualene cyclase.J. Steroid Biochem. Mol. Biol.201918518919910.1016/j.jsbmb.2018.09.001 30193921
     [Google Scholar]
  66. RegasiniL.O. Martins de OliveiraC. JoséC.R.V. olga maria mascarenhas de faria oliveira, dulce helena siqueira silva, vanderlan da silva bolzani. free radical scavenging activity of pterogyne nitens tul. (fabaceae).Afr. J. Biotechnol.200872446094613
     [Google Scholar]
  67. RegasiniL.O. VellosaJ.C.R. SilvaD.H.S. FurlanM. de OliveiraO.M.M. KhalilN.M. BrunettiI.L. YoungM.C.M. BarreiroE.J. BolzaniV.S. Flavonols from Pterogyne nitens and their evaluation as myeloperoxidase inhibitors.Phytochemistry20086981739174410.1016/j.phytochem.2008.01.006 18395762
     [Google Scholar]
  68. GalloM.B.C. MarquesA.S.F. VieiraP.C. da SilvaM.F.G.F. FernandesJ.B. SilvaM. GuidoR.V. OlivaG. ThiemannO.H. AlbuquerqueS. FairlambA.H. Enzymatic inhibitory activity and trypanocidal effects of extracts and compounds from Siphoneugena densiflora O. Berg and Vitex polygama Cham.Z. Naturforsch. C J. Biosci.2008635-637138210.1515/znc‑2008‑5‑611 18669023
     [Google Scholar]
  69. de SousaL.R.F. RamalhoS.D. BurgerM.C.M. NeboL. FernandesJ.B. da SilvaM.F.G.F. IemmaM.R.C. CorrêaC.J. SouzaD.H.F. LimaM.I.S. VieiraP.C. Isolation of arginase inhibitors from the bioactivity-guided fractionation of Byrsonima coccolobifolia leaves and stems.J. Nat. Prod.201477239239610.1021/np400717m 24521209
     [Google Scholar]
  70. GalloM.B.C. RochaW.C. da CunhaU.S. DiogoF.A. da SilvaF.C. VieiraP.C. VendramimJ.D. FernandesJ.B. da SilvaM.F.G.F. Batista-PereiraL.G. Bioactivity of extracts and isolated compounds fromVitex polygama (Verbenaceae) and Siphoneugena densiflora (Myrtaceae) againstSpodoptera frugiperda (Lepidoptera: Noctuidae).Pest Manag. Sci.200662111072108110.1002/ps.1278 16953496
     [Google Scholar]
  71. HamerskiL. CarboneziC.A. CavalheiroA.J. BolzaniV.S. YoungM.C.M. Saponinas triterpênicas de Tocoyena brasiliensis Mart. (Rubiaceae).Quim. Nova200528460160410.1590/S0100‑40422005000400009
     [Google Scholar]
  72. BolzaniV.D.S. GunatilakaA.A.L. KingstonD.G.I. Bioactive guanidine alkaloids from pterogyne nitens.J. Nat. Prod.199558111683168810.1021/np50125a006
     [Google Scholar]
  73. FernandesD.C. RegasiniL.O. VellosaJ.C.R. PaulettiP.M. Castro-gamboaI. BolzaniV.S. OliveiraO.M.M. SilvaD.H.S. Myeloperoxidase inhibitory and radical scavenging activities of flavones from Pterogyne nitens.Chem. Pharm. Bull.200856572372610.1248/cpb.56.723 18451567
     [Google Scholar]
  74. SilvaV.C. BolzaniV.S. YoungM.C.M. LopesM.N. A new antifungal phenolic glycoside derivative, iridoids and lignans from Alibertia sessilis (vell.) k. schum. (Rubiaceae).J. Braz. Chem. Soc.20071871405140910.1590/S0103‑50532007000700017
     [Google Scholar]
  75. BolzaniV.S. TrevisanL.M.V. IzumisawaC.M. YoungM.C.M. Antifungal iridoids from the stems of tocoyena formosa.J. Braz. Chem. Soc.19967315716010.5935/0103‑5053.19960024
     [Google Scholar]
  76. RegasiniL.O. FernandesD.C. Castro-GamboaI. SilvaD.H.S. FurlanM. Bolzani, V. da. S.; Barreiro, E.J.; Cardoso-Lopes, E.M.; Young, M.C.M.; Torres, L.B Constituintes químicos das flores de pterogyne nitens (caesalpinioideae).Quim. Nova2008314802806
     [Google Scholar]
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Exploring Brazilian Natural Products as Potential Bioactive Compounds against Trypanosoma cruzi by Targeting Squalene Synthase
Letters in Drug Design & Discovery 21, 2777 (2024); https://doi.org/10.2174/1570180820666230816141241
/content/journals/lddd/10.2174/1570180820666230816141241
/content/journals/lddd/10.2174/1570180820666230816141241
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  • Article Type:     Letter
Keyword(s): Chagas disease; ergosterol biosynthesis; molecular modeling; natural products; neglected tropical diseases; squalene synthase

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