Abstract
We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a “jaw opening” gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays. This strategy was successful as all 13 tested molecules suggested from the in silico calculations were found out to be active POPTc80 inhibitors in the micromolar range (lowest K i at 667 nM). This work paves the way for future development of innovative drugs against Chagas disease.
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References
Haberland A et al (2013) Chronic Chagas disease: from basics to laboratory medicine. Clin Chem Lab Med 51:271–294
Nunes MCP et al (2013) Chagas disease: an overview of clinical and epidemiological aspects. J Am Coll Cardiol 62:767–776
Dias JCP, Silveira AC, Schofield CJ (2002) The impact of Chagas disease control in Latin America: a review. Mem Inst Oswaldo Cruz 97:603–612
de Castro SL (1993) The challenge of Chagas’ disease chemotherapy: an update of drugs assayed against Trypanosoma cruzi. Acta Trop 53:83–98
Rodriques Coura J, de Castro SL (2002) A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 97:3–24
Urbina JA, Docampo R (2003) Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol 19:495–501
Croft SL, Barrett MP, Urbina JA (2005) Chemotherapy of trypanosomiases and leishmaniasis. Trends Parasitol 21:508–512
Savioli L et al (2010) Working to overcome the global impact of neglected tropical diseases: first WHO report on neglected tropical diseases. World Health Organization Geneva, Switzerland
Santana J et al (1997) A Trypanosoma cruzi-secreted 80 kDa proteinase with specificity for human collagen types I and IV. Biochem J 137:129–137
Grellier P et al (2001) Trypanosoma cruzi prolyl oligopeptidase Tc80 is involved in nonphagocytic mammalian cell invasion by trypomastigotes. J Biol Chem 276:47078–47086
Dourado Bastos IM et al (2005) Molecular, functional and structural properties of the prolyl oligopeptidase of Trypanosoma cruzi (POP Tc80), which is required for parasite entry into mammalian cells. Biochem J 388:29–38
Vendeville S et al (1999) Identification of inhibitors of an 80 kDa protease from Trypanosoma cruzi through the screening of a combinatorial peptide library. Chem Pharm Bull 47:194–198
Joyeau R et al (2000) Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi. Eur J Med Chem 35:257–266
Bal G et al (2003) Prolylisoxazoles: potent inhibitors of prolyloligopeptidase with antitrypanosomal activity. Bioorg Med Chem Lett 13:2875–2878
Choe Y et al (2005) Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease. Bioorg Med Chem 13:2141–2156
Dourado Bastos IM et al (2013) Parasite prolyl oligopeptidases and the challenge of designing chemotherapeuticals for Chagas disease, leishmaniasis and African trypanosomiasis. Curr Med Chem 20:3103–3115
Maluf FV et al (2013) A pharmacophore-based virtual screening approach for the discovery of Trypanosoma cruzi GAPDH inhibitors. Future Med Chem 5:2019–2035
Meiering S et al (2005) Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. J Med Chem 48:4793–4802
Cavasotto CN, Phatak SS (2009) Homology modeling in drug discovery: current trends and applications. Drug Discov Today 14:676–683
Du H et al (2015) Protein structure prediction provides comparable performance to crystallographic structures in docking-based virtual screening. Methods 71:77–84
Fülöp V, Böcskei Z, Polgár L (1998) Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis. Cell 94:161–170
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38
Phillips JC et al (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802
MacKerell AD et al (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616
Iturrioz X et al (2010) By interacting with the C-terminal Phe of apelin, Phe255 and Trp259 in helix VI of the apelin receptor are critical for internalization. J Biol Chem 285:32627–32637
Cai W, Shao X, Maigret B (2002) Protein–ligand recognition using spherical harmonic molecular surfaces: towards a fast and efficient filter for large virtual throughput screening. J Mol Graph Model 20:313–328
Cai W et al (2008) SHEF: a vHTS geometrical filter using coefficients of spherical harmonic molecular surfaces. J Mol Model 14:393–401
Weidel E et al (2014) Composing compound libraries for hit discovery—rationality-driven preselection or random choice by structural diversity? Future Med Chem 6:2057–2072
López A, Tarragó T, Giralt E (2011) Low molecular weight inhibitors of prolyl oligopeptidase: a review of compounds patented from 2003 to 2010. Expert Opin Ther Pat 21:1023–1044
Pripp AH (2006) Quantitative structure—activity relationship of prolyl oligopeptidase inhibitory peptides derived from β-casein using simple amino acid descriptors. J Agric Food Chem 54:224–228
Sadowski J, Gasteiger J (1993) From atoms and bonds to three-dimensional atomic coordinates: automatic model builders. Chem Rev 93:2567–2581
Sadowski J, Gasteiger J, Klebe G (1994) Comparison of automatic three-dimensional model builders using 639 X-ray structures. J Chem Inf Model 34:1000–1008
Verdonk ML et al (2003) Improved protein–ligand docking using GOLD. Proteins 52:609–623
Cornish-Bowden A (1976) Principles of enzyme kinetics. Butterworths, London
Salvesen G, Nagase H (1989) Inhibition of proteolytic enzymes. In: Bond JS, Beynon RJ (eds) Proteolytic enzymes: a practical approach. IRL Press, Oxford, pp 83–104
Haffner CD et al (2008) Pyrrolidinyl pyridone and pyrazinone analogues as potent inhibitors of prolyl oligopeptidase (POP). Bioorg Med Chem Lett 18:4360–4363
Devine SM et al (2015) Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold. J Med Chem 58:1205–1214
Baell J, Walters MA (2014) Chemical con artists foil drug discovery. Nature 513:481–483
Irwin JJ et al (2015) An aggregation advisor for ligand discovery. J Med Chem 58:7076–7087
Ferreira RS et al (2010) Complementarity between a docking and a high-throughput screen in discovering new Cruzain inhibitors. J Med Chem 53:4891–4905
Feng BY, Shoichet BK (2006) A detergent-based assay for the detection of promiscuous inhibitors. Nat Protoc 1:550–553
Acknowledgments
This work was supported by CAPES-COFECUB N°723/11, CNPq, MCTI/CNPq/FNDCT/PRO-CENTRO-OESTE 407730/2013-3, FAPDF, FINEP and the Grant N°1891.7 between CNRS and CNPq. We thank the MBI project at LORIA for computer facilities.
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Hugo de Almeida and Vincent Leroux have contributed equally to this work.
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de Almeida, H., Leroux, V., Motta, F.N. et al. Identification of novel Trypanosoma cruzi prolyl oligopeptidase inhibitors by structure-based virtual screening. J Comput Aided Mol Des 30, 1165–1174 (2016). https://doi.org/10.1007/s10822-016-9985-1
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DOI: https://doi.org/10.1007/s10822-016-9985-1