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A computer-aided approach to identify novel Leishmania major protein disulfide isomerase inhibitors for treatment of leishmaniasis

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Abstract

Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania and transmitted by the bite of a sand fly. To date, most available drugs for treatment are toxic and beyond the economic means of those affected by the disease. Protein disulfide isomerase (PDI) is a chaperone protein that plays a major role in the folding of newly synthesized proteins, specifically assisting in disulfide bond formation, breakage, or rearrangement in all non-native proteins. In previous work, we demonstrated that Leishmania major PDI (LmPDI) has an essential role in pathogen virulence. Furthermore, inhibition of LmPDI further blocked parasite infection in macrophages. In this study, we utilized a computer-aided approach to design a series of LmPDI inhibitors. Fragment-based virtual screening allowed for the understanding of the inhibitors’ modes of action on LmPDI active sites. The generated compounds obtained after multiple rounds of virtual screening were synthesized and significantly inhibited target LmPDI reductase activity and were shown to decrease in vitro parasite growth in human monocyte-derived macrophages. This novel cheminformatics and synthetic approach led to the identification of a new series of compounds that might be optimized into novel drugs, likely more specific and less toxic for the treatment of leishmaniasis.

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Data availability

All data and material used in this study is available.

Code availability

The “Small-Molecule Drug Discovery Suite v. 2014” Software package of Schrödinger was used in the study.

References

  1. Akhoundi M, Downing T, Votypka J, Kuhls K, Lukes J, Cannet A, Ravel C, Marty P, Delaunay P, Kasbari M, Granouillac B, Gradoni L, Sereno D (2017) Mol Aspects Med 57:1

    Article  CAS  PubMed  Google Scholar 

  2. Cunningham AC (2002) Exp Mol Pathol 72(2):132

    Article  CAS  PubMed  Google Scholar 

  3. Postigo JA (2010) Int J Antimicrob Agents 36(Suppl 1):S62

    Article  CAS  PubMed  Google Scholar 

  4. Postigo JA (2011) Wkly Epidemiol Rec 86(13):113

    Google Scholar 

  5. Amato VS, Tuon FF, Bacha HA, Neto VA, Nicodemo AC (2008) Acta Trop 105(1):1

    Article  CAS  PubMed  Google Scholar 

  6. van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M (2010) Lancet Infect Dis 10(3):184

    Article  PubMed  Google Scholar 

  7. Ait-Oudhia K, Gazanion E, Vergnes B, Oury B, Sereno D (2011) Parasitol Res 109(5):1225

    Article  PubMed  Google Scholar 

  8. Uliana SRB, Trinconi CT, Coelho AC (2018) Parasitology 145(4):464

    Article  PubMed  CAS  Google Scholar 

  9. Ponte-Sucre A, Gamarro F, Dujardin JC, Barrett MP, Lopez-Velez R, Garcia-Hernandez R, Pountain AW, Mwenechanya R, Papadopoulou B (2017) PLoS Negl Trop Dis 11(12):e0006052

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Rijal S, Ostyn B, Uranw S, Rai K, Bhattarai NR, Dorlo TP, Beijnen JH, Vanaerschot M, Decuypere S, Dhakal SS, Das ML, Karki P, Singh R, Boelaert M, Dujardin JC (2013) Clin Infect Dis 56(11):1530

    Article  CAS  PubMed  Google Scholar 

  11. de Menezes JP, Guedes CE, Petersen AL, Fraga DB, Veras PS (2015) Biomed Res Int 2015:815023

    PubMed  PubMed Central  Google Scholar 

  12. Ferreira LLG, Andricopulo AD (2018) Front Pharmacol 9:1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krauth-Siegel RL, Comini MA (2008) Biochim Biophys Acta 1780(11):1236

    Article  CAS  PubMed  Google Scholar 

  14. Krauth-Siegel RL, Coombs GH (1999) Parasitol Today 15(10):404

    Article  CAS  PubMed  Google Scholar 

  15. Hatahet F, Ruddock LW (2009) Antioxid Redox Signal 11(11):2807

    Article  CAS  PubMed  Google Scholar 

  16. Stolf BS, Smyrnias I, Lopes LR, Vendramin A, Goto H, Laurindo FR, Shah AM, Santos CX (2011) Sci World J 11:1749

    Article  CAS  Google Scholar 

  17. Ben Achour Y, Chenik M, Louzir H, Dellagi K (2002) Infect Immun 70(7):3576

    Article  CAS  PubMed  Google Scholar 

  18. Brauer P, Parker JL, Gerondopoulos A, Zimmermann I, Seeger MA, Barr FA, Newstead S (2019) Science 363(6431):1103

    Article  PubMed  CAS  Google Scholar 

  19. Ben Khalaf N, De Muylder G, Louzir H, McKerrow J, Chenik M (2012) Parasitol Res 110(5):1911

    Article  PubMed  Google Scholar 

  20. Ben Khalaf N, De Muylder G, Ratnam J, Kean-Hooi Ang K, Arkin M, McKerrow J, Chenik M (2011) J Biomol Screen 16(5):545

    Article  CAS  PubMed  Google Scholar 

  21. Repasky MP, Shelley M, Friesner RA (2007) Curr Protoc Bioinformatics 8:812

  22. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) J Mol Biol 215(3):403

    Article  CAS  PubMed  Google Scholar 

  23. Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H (2006) Cell 124(1):61

    Article  CAS  PubMed  Google Scholar 

  24. Mazanetz MP, Marmon RJ, Reisser CB, Morao I (2012) Curr Top Med Chem 12(18):1965

    Article  CAS  PubMed  Google Scholar 

  25. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B, Shaw DE, Friesner RA (2004) Proteins 55(2):351

    Article  CAS  PubMed  Google Scholar 

  26. Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM (1996) J Biomol NMR 8(4):477

    Article  CAS  PubMed  Google Scholar 

  27. Bordoli L, Schwede T (2012) Methods Mol Biol 857:107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Eswar N, Eramian D, Webb B, Shen MY, Sali A (2008) Methods Mol Biol 426:145

    Article  CAS  PubMed  Google Scholar 

  29. Sterling T, Irwin JJ (2015) J Chem Inf Model 55(11):2324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lipinski CA (2000) J Pharmacol Toxicol Methods 44(1):235

    Article  CAS  PubMed  Google Scholar 

  31. Bajusz D, Racz A, Heberger K (2015) J Chem Inform 7:20

    Google Scholar 

  32. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) J Med Chem 47(7):1739

    Article  CAS  PubMed  Google Scholar 

  33. Daina A, Michielin O, Zoete V (2017) Sci Rep 7:42717

    Article  PubMed  PubMed Central  Google Scholar 

  34. Stokker GE, Deana AA, deSolms SJ, Schultz EM, Smith RL, Cragoe EJ Jr, Baer JE, Ludden CT, Russo HF, Scriabine A, Sweet CS, Watson LS (1980) J Med Chem 23(12):1414

    Article  CAS  PubMed  Google Scholar 

  35. Holmgren A (1979) J Biol Chem 254(19):9627

    Article  CAS  PubMed  Google Scholar 

  36. Spath GF, Beverley SM (2001) Exp Parasitol 99(2):97

    Article  CAS  PubMed  Google Scholar 

  37. Skagerberg B, Clementi S, Sjostrom M, Tosato ML, Wold S (1989) Prog Clin Biol Res 291:127

    CAS  PubMed  Google Scholar 

  38. Copeland NK, Aronson NE (2015) Curr Opin Infect Dis 28(5):426

    Article  CAS  PubMed  Google Scholar 

  39. Sunyoto T, Potet J, Boelaert M (2018) BMJ Glob Health 3(3):e000709

    Article  PubMed  PubMed Central  Google Scholar 

  40. Preston S, Gasser RB (2018) Trends Parasitol 34(1):4

    Article  PubMed  Google Scholar 

  41. Folmer RH (2016) Drug Discov Today 21(3):491

    Article  CAS  PubMed  Google Scholar 

  42. Liu R, Li X, Lam KS (2017) Curr Opin Chem Biol 38:117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ponder EL, Freundlich JS, Sarker M, Ekins S (2014) Pharm Res 31(2):271

    Article  CAS  PubMed  Google Scholar 

  44. Macalino SJ, Gosu V, Hong S, Choi S (2015) Arch Pharm Res 38(9):1686

    Article  CAS  PubMed  Google Scholar 

  45. Ong HB, Sienkiewicz N, Wyllie S, Fairlamb AH (2011) J Biol Chem 286(12):10429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rashid U, Sultana R, Shaheen N, Hassan SF, Yaqoob F, Ahmad MJ, Iftikhar F, Sultana N, Asghar S, Yasinzai M, Ansari FL, Qureshi NA (2016) Eur J Med Chem 115:230

    Article  CAS  PubMed  Google Scholar 

  47. De Luca L, Ferro S, Buemi MR, Monforte AM, Gitto R, Schirmeister T, Maes L, Rescifina A, Micale N (2018) Chem Biol Drug Des 92(3):1585

    Article  PubMed  CAS  Google Scholar 

  48. Ochoa R, Watowich SJ, Florez A, Mesa CV, Robledo SM, Muskus C (2016) J Comput Aided Mol Des 30(7):541

    Article  CAS  PubMed  Google Scholar 

  49. King GJ, Chen KE, Robin G, Forwood JK, Heras B, Thakur AS, Kobe B, Blomberg SP, Martin JL (2009) PLoS ONE 4(11):e7851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Liao M, Ma L, Bannai H, Lee EG, Xie Z, Tang X, Zhang H, Xuan X, Fujisaki K (2006) Vet Parasitol 139(1–3):47

    Article  CAS  PubMed  Google Scholar 

  51. Florent I, Mouray E, Dali Ali F, Drobecq H, Girault S, Schrevel J, Sergheraert C, Grellier P (2000) FEBS Lett 484(3):246

    Article  CAS  PubMed  Google Scholar 

  52. Joshi S, Yadav NK, Rawat K, Kumar V, Ali R, Sahasrabuddhe AA, Siddiqi MI, Haq W, Sundar S, Dube A (2019) Front Immunol 10:288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. He J, Huang F, Li J, Chen Q, Chen D, Chen J (2019) Acta Trop 191:50

    Article  CAS  PubMed  Google Scholar 

  54. Amit A, Vijayamahantesh, Dikhit MR, Singh AK, Kumar V, Suman SS, Singh A, Kumar A, Thakur AK, Das VR, Das P, Bimal S (2017) Mol Immunol 82:104

    Article  CAS  PubMed  Google Scholar 

  55. Markikou-Ouni W, Ben Achour-Chenik Y, Meddeb-Garnaoui A (2012) Clin Exp Immunol 169(3):273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Poole LB (2015) Free Radic Biol Med 80:148

    Article  CAS  PubMed  Google Scholar 

  57. Lorusso DJ, Miller TL (1981) Res Commun Chem Pathol Pharmacol 31(2):205

    CAS  PubMed  Google Scholar 

  58. Shuman RM, Leech RW, Alvord EC Jr (1974) Pediatrics 54(6):689

    Article  CAS  PubMed  Google Scholar 

  59. Shuman RM, Leech RW, Alvord EC Jr (1975) Arch Neurol 32(5):320

    Article  CAS  PubMed  Google Scholar 

  60. Lampert P, O’Brien J, Garrett R (1973) Acta Neuropathol 23(4):326

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was funded by an Internal Grant of the Arabian Gulf University.

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Authors and Affiliations

  1. Department of Life Sciences, Health Biotechnology Program, College of Graduates Studies, King Fahd Chair for Health Biotechnology, Arabian Gulf University, Road 2904 Building 293, Manama, 329, Kingdom of Bahrain

    Noureddine Ben Khalaf & Dahmani M. Fathallah

  2. Center for Global Health, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Susie Pham, Peter Sedillo, Jessica Gonzales, Douglas J. Perkins & Ivy Hurwitz

  3. Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125, Catania, Italy

    Giuseppe Romeo, Sebastiano Intagliata, Loredana Salerno & Valeria Pittalà

  4. Department of Molecular Medicine, Princess Al-Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain

    Sara Abdelghany

Authors
  1. Noureddine Ben Khalaf
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  2. Susie Pham
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  5. Sebastiano Intagliata
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  8. Jessica Gonzales
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  9. Dahmani M. Fathallah
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  10. Douglas J. Perkins
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  11. Ivy Hurwitz
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  12. Valeria Pittalà
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by NBK, SP, SA, GR, SI, LS, PS, JG, DJP, DMF, IH and VP. The first draft of the manuscript was written by NBK, SP, IH and VP, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Noureddine Ben Khalaf.

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The authors declare no conflict of interest or competing interests.

Ethics approval

PBMCs were isolated from blood of healthy, unidentified donors of both sexes procured from United Blood services (Approved contract #120913, Dr. Douglas Perkins, UNM HSC). This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of New Mexico.

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Ben Khalaf, N., Pham, S., Romeo, G. et al. A computer-aided approach to identify novel Leishmania major protein disulfide isomerase inhibitors for treatment of leishmaniasis. J Comput Aided Mol Des 35, 297–314 (2021). https://doi.org/10.1007/s10822-021-00374-w

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  • DOI: https://doi.org/10.1007/s10822-021-00374-w

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