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Theoretical study of new LmDHODH and LmTXNPx complexes: structure-based relationships

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Abstract

In this work, a series of eight novel ring-substituted styrylquinolines were synthesized, and in silico physicochemical properties were estimated. The inhibitory activity of these compounds was evaluated in intracellular amastigotes of Leishmania (Viannia) panamensis, and their affinity for L. major dihydroorotate dehydrogenase DHODH (LmDHODH) and L. major tryparedoxin peroxidase TXNPx (LmTXNPx) was calculated by molecular docking, NCI index, and the recently developed IGM analysis, providing us useful insights about the forces governing the ligand-protein coupling. The eight synthesized molecules do not break the Lipinski, Ghose, Veber, Egan, and Muegge rules. Therefore, the bioavailability and absorption will not be poor.

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References

  1. Ferreira LLG, Andricopulo AD (2018) Chemoinformatics strategies for leishmaniasis drug discovery. Front Pharmacol 9:1278. https://doi.org/10.3389/fphar.2018.01278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bonardi A, Vermelho AB, Da Silva CV et al (2019) N-Nitrosulfonamides as carbonic anhydrase inhibitors: a promising chemotype for targeting Chagas disease and Leishmaniasis. ACS Med Chem Lett 10:413–418. https://doi.org/10.1021/acsmedchemlett.8b00430

    Article  CAS  PubMed  Google Scholar 

  3. Ochoa R, Watowich SJ, Flórez A et al (2016) Drug search for leishmaniasis: a virtual screening approach by grid computing. J Comput Aided Mol Des 30:541–552. https://doi.org/10.1007/s10822-016-9921-4

    Article  CAS  PubMed  Google Scholar 

  4. Bermúdez H, Rojas E, Garcia L et al (2006) Generic sodium stibogluconate is as safe and effective as branded meglumine antimoniate, for the treatment of tegumentary leishmaniasis in Isiboro Secure Park, Bolivia. Ann Trop Med Parasitol 100:591–600. https://doi.org/10.1179/136485906X118495

    Article  CAS  PubMed  Google Scholar 

  5. Layegh P, Yazdanpanah MJ, Vosugh EM et al (2007) Efficacy of azithromycin versus systemic meglumine antimoniate (glucantime) in the treatment of cutaneous leishmaniasis. Am J Trop Med Hyg 77:99–101. https://doi.org/10.4269/ajtmh.2007.77.99

    Article  CAS  PubMed  Google Scholar 

  6. Frézard F, Demicheli C, Ribeiro R (2009) Pentavalent antimonials: new perspectives for old drugs. Molecules 14:2317–2336. https://doi.org/10.3390/molecules14072317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mackey TK, Liang BA, Cuomo R et al (2014) Emerging and reemerging neglected tropical diseases: a review of key characteristics. Risk Factors, and the Policy and Innovation Environment. https://doi.org/10.1128/CMR.00045-14

  8. Barrett MP, Croft SL (2012) Management of trypanosomiasis and leishmaniasis. Br Med Bull 104:175–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guedes PMM, Silva GK, Gutierrez FRS, Silva JS (2011) Current status of Chagas disease chemotherapy. Expert Rev Anti-Infect Ther 9:609–620

    Article  PubMed  Google Scholar 

  10. El-Sayed MAA, El-Husseiny WM, Abdel-Aziz NI et al (2018) Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study. J Enzyme Inhib Med Chem 33:199–209. https://doi.org/10.1080/14756366.2017.1407926

    Article  CAS  PubMed  Google Scholar 

  11. Richard JV, Werbovetz KA (2010) New antileishmanial candidates and lead compounds. Curr Opin Chem Biol 14:447–455

    Article  CAS  PubMed  Google Scholar 

  12. Delattin N, Bardiot D, Marchand A et al (2012) Identification of fungicidal 2,6-disubstituted quinolines with activity against candida biofilms. Molecules 17:12243–12251. https://doi.org/10.3390/molecules171012243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Afzal O, Kumar S, Haider MR et al (2015) A review on anticancer potential of bioactive heterocycle quinoline. Eur J Med Chem 97:871–910

    Article  CAS  PubMed  Google Scholar 

  14. Pálinkó I, Kukovecz Á, Török B, Körtvélyesi T (2000) On the mechanism of a modified Perkin condensation leading to α-phenylcinnamic acid stereoisomers - experiments and molecular modelling. Monatshefte fur Chemie 131:1097–1104. https://doi.org/10.1007/s007060070043

    Article  Google Scholar 

  15. Pawar PM, Jarag KJ, Shankarling GS (2011) Environmentally benign and energy efficient methodology for condensation: an interesting facet to the classical Perkin reaction. Green Chem 13:2130–2134. https://doi.org/10.1039/c0gc00712a

    Article  CAS  Google Scholar 

  16. Brindisi M, Brogi S, Relitti N et al (2015) Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking. Sci Rep 5:9705. https://doi.org/10.1038/srep09705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Coa JC, Castrillón W, Cardona W et al (2015) Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline-hydrazone hybrids. Eur J Med Chem 101:746–753. https://doi.org/10.1016/j.ejmech.2015.07.018

    Article  CAS  PubMed  Google Scholar 

  18. Zouhiri F, Desmaële D, D’Angelo J et al (2001) HIV-1 replication inhibitors of the styrylquinoline class: incorporation of a masked diketo acid pharmacophore. Tetrahedron Lett 42:8189–8192. https://doi.org/10.1016/S0040-4039(01)01767-1

    Article  CAS  Google Scholar 

  19. Escobar P, Matu S, Marques C, Croft SL (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH3 (edelfosine) and amphotericin B. Acta Trop 81:151–157. https://doi.org/10.1016/S0001-706X(01)00197-8

    Article  CAS  PubMed  Google Scholar 

  20. Vageli DP, Doukas SG, Spock T, Sasaki CT (2018) Curcumin prevents the bile reflux-induced NF-κB-related mRNA oncogenic phenotype, in human hypopharyngeal cells. J Cell Mol Med 22:4209–4220. https://doi.org/10.1111/jcmm.13701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:1–13. https://doi.org/10.1038/srep42717

    Article  Google Scholar 

  22. Cheleski J, Rocha JR, Pinheiro MP et al (2010) Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery. Eur J Med Chem 45:5899–5909. https://doi.org/10.1016/j.ejmech.2010.09.055

    Article  CAS  PubMed  Google Scholar 

  23. Cordeiro AT, Feliciano PR, Pinheiro MP, Nonato MC (2012) Crystal structure of dihydroorotate dehydrogenase from Leishmania major. Biochimie 94:1739–1748. https://doi.org/10.1016/j.biochi.2012.04.003

    Article  CAS  PubMed  Google Scholar 

  24. Fiorillo A, Colotti G, Boffi A et al (2012) The crystal structures of the tryparedoxin-tryparedoxin peroxidase couple unveil the structural determinants of Leishmania detoxification pathway. PLoS Negl Trop Dis 6. https://doi.org/10.1371/journal.pntd.0001781

  25. Trott O, Olson A (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334.AutoDock

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stewart JJP (2016) MOPAC

  27. Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model 13:1173–1213. https://doi.org/10.1007/s00894-007-0233-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dassault Systèmes BIOVIA (2017) Discovery Studio Modeling Environment

  29. Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:55–84. https://doi.org/10.1016/S1093-3263(99)99999-0

    Article  Google Scholar 

  30. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36:3219–3228. https://doi.org/10.1016/0040-4020(80)80168-2

    Article  CAS  Google Scholar 

  31. Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28:235–242. https://doi.org/10.1093/nar/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Madhavi Sastry G, Adzhigirey M, Day T et al (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234. https://doi.org/10.1007/s10822-013-9644-8

    Article  CAS  PubMed  Google Scholar 

  33. Schrödinger Release 2020–1: Maestro, Schrödinger,... - Google Académico. https://scholar.google.com/scholar?hl=es&as_sdt=0%2C5&q=Schrödinger+Release+2020-1%3A+Maestro%2C+Schrödinger%2C+LLC%2C+New+York%2C+NY%2C+2020&btnG=. Accessed 17 Mar 2020

  34. Johnson ER, Keinan S, Mori-Sánchez P et al (2010) Revealing noncovalent interactions. J Am Chem Soc 132:6498–6506. https://doi.org/10.1021/ja100936w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Contreras-García J, Johnson ER, Keinan S et al (2011) NCIPLOT: a program for plotting noncovalent interaction regions. J Chem Theory Comput 7:625–632. https://doi.org/10.1021/ct100641a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  PubMed  Google Scholar 

  37. IGMPlot: a program revealing non-covalent interactions. http://igmplot.univ-reims.fr. Accessed 13 Jul 2020

  38. Ponce-Vargas M, Lefebvre C, Boisson JC, Hénon E (2020) Atomic decomposition scheme of noncovalent interactions applied to host-guest assemblies. J Chem Inf Model 60:268–278. https://doi.org/10.1021/acs.jcim.9b01016

    Article  CAS  PubMed  Google Scholar 

  39. Luzina E, Chemistry AP-J of F, 2013 U (2013) Synthesis of 1-aroyl (1-arylsulfonyl)-4-bis (trifluoromethyl) alkyl semicarbazides as potential physiologically active compounds. Elsevier 148:41–48

    CAS  Google Scholar 

  40. Luzina EL, Popov AV (2014) Synthesis and anticancer activity evaluation of 3,4-mono- and bicyclosubstituted N-(het)aryl trifluoromethyl succinimides. J Fluor Chem 168:121–127. https://doi.org/10.1016/j.jfluchem.2014.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang X, Lu K, Luo H et al (2018) In silico identification of small molecules as novel LXR agonists for the treatment of cardiovascular disease and cancer. J Mol Model 24:24–57. https://doi.org/10.1007/s00894-018-3578-y

    Article  CAS  Google Scholar 

  42. Aly AA, Sayed SM, Abdelhafez ESM, Abdelhafez SMN, Abdelzaher WY, Raslan MA et al (2020) New quinoline-2-one/pyrazole derivatives; design, synthesis, molecular docking, anti-apoptotic evaluation, and caspase-3 inhibition assay. Bioorg Chem 94:103348

    Article  CAS  PubMed  Google Scholar 

  43. Chibli LA, Schmidt TJ, Nonato MC et al (2018) Natural products as inhibitors of Leishmania major dihydroorotate dehydrogenase. Eur J Med Chem 157:852–866. https://doi.org/10.1016/j.ejmech.2018.08.033

    Article  CAS  PubMed  Google Scholar 

  44. Piñeyro MD, Pizarro JC, Lema F et al (2005) Crystal structure of the tryparedoxin peroxidase from the human parasite Trypanosoma cruzi. J Struct Biol 150:11–22. https://doi.org/10.1016/j.jsb.2004.12.005

    Article  CAS  PubMed  Google Scholar 

  45. Ogungbe IV, Erwin WR, Setzer WN (2014) Antileishmanial phytochemical phenolics: molecular docking to potential protein targets. J Mol Graph Model 48:105–117. https://doi.org/10.1016/j.jmgm.2013.12.010

    Article  CAS  PubMed  Google Scholar 

  46. Wachsmuth LM, Johnson MG, Gavenonis J (2017) Essential multimeric enzymes in kinetoplastid parasites: a host of potentially druggable protein-protein interactions. PLoS Negl Trop Dis 11:1–16. https://doi.org/10.1371/journal.pntd.0005720

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Relativistic Molecular Physics Group (ReMoPh), PhD program in Molecular Physical Chemistry, Facultad de Ciencias Exactas, Universidad Andres Bello, República 275, Santiago, Chile

    Plinio Cantero-López

  2. Center of Applied Nanoscience (CANS), Facultad de Ciencias Exactas, Universidad Andres Bello, Av. República 330, Santiago, Chile

    Plinio Cantero-López

  3. PECET-Programa de Estudio y Control de Enfermedades Tropicales. Facultad de Medicina, Universidad de Antioquia, Calle 70 No. 52–21, Medellín, A 1226, Colombia

    Sara M. Robledo Restrepo

  4. Computational and Theoretical Chemistry Group, Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andrés Bello, República 498, Santiago, Chile

    Osvaldo Yañez

  5. Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias de la Vida, Universidad Andres Bello, Av. Republica ́ 330, 8370146, Santiago, Chile

    Osvaldo Yañez

  6. Center of New Drugs for Hypertension (CENDHY), Santiago, Chile

    Osvaldo Yañez

  7. Instituto de Ciencias Naturales, Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Sede Providencia, Manuel Montt 948, 7500972, Santiago, Chile

    César Zúñiga

  8. Facultad de Ciencias de la Salud, Universidad Central de Chile, Lord Cochrane 417, Santiago, Chile

    César Zúñiga

  9. Grupo de Investigación Química de los Productos Naturales, Departamento de Química, Universidad de Córdoba, Carrera6 Núm.76-103, Montería, Córdoba, Colombia

    Gilmar G. Santafé-Patiño

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  1. Plinio Cantero-López
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  5. Gilmar G. Santafé-Patiño
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Correspondence to Plinio Cantero-López.

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Cantero-López, P., Robledo Restrepo, S.M., Yañez, O. et al. Theoretical study of new LmDHODH and LmTXNPx complexes: structure-based relationships. Struct Chem 32, 167–177 (2021). https://doi.org/10.1007/s11224-020-01624-7

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