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Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake.

Abstract

Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in Trypanosoma cruzi, an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease TcPAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from Escherichia coli as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against T. cruzi epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake.

Authors+Show Affiliations

Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET) Buenos Aires, Argentina.Department of Microbiology, Parasitology and Immunology, School of Medicine, Institute of Microbiology and Medical Parasitology (CONICET), University of Buenos Aires Buenos Aires, Argentina.Department of Microbiology, Parasitology and Immunology, School of Medicine, Institute of Microbiology and Medical Parasitology (CONICET), University of Buenos Aires Buenos Aires, Argentina.Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET) Buenos Aires, Argentina.Department of Microbiology, Parasitology and Immunology, School of Medicine, Institute of Microbiology and Medical Parasitology (CONICET), University of Buenos Aires Buenos Aires, Argentina.Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET) Buenos Aires, Argentina.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata Buenos Aires, Argentina.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29888213

Citation

Alberca, Lucas N., et al. "Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake." Frontiers in Cellular and Infection Microbiology, vol. 8, 2018, p. 173.
Alberca LN, Sbaraglini ML, Morales JF, et al. Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake. Front Cell Infect Microbiol. 2018;8:173.
Alberca, L. N., Sbaraglini, M. L., Morales, J. F., Dietrich, R., Ruiz, M. D., Pino Martínez, A. M., ... Talevi, A. (2018). Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake. Frontiers in Cellular and Infection Microbiology, 8, p. 173. doi:10.3389/fcimb.2018.00173.
Alberca LN, et al. Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake. Front Cell Infect Microbiol. 2018;8:173. PubMed PMID: 29888213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake. AU - Alberca,Lucas N, AU - Sbaraglini,María L, AU - Morales,Juan F, AU - Dietrich,Roque, AU - Ruiz,María D, AU - Pino Martínez,Agustina M, AU - Miranda,Cristian G, AU - Fraccaroli,Laura, AU - Alba Soto,Catalina D, AU - Carrillo,Carolina, AU - Palestro,Pablo H, AU - Talevi,Alan, Y1 - 2018/05/25/ PY - 2017/12/21/received PY - 2018/05/04/accepted PY - 2018/6/12/entrez PY - 2018/6/12/pubmed PY - 2019/6/14/medline KW - Chagas disease KW - Trypanosoma cruzi KW - cinnarizine KW - drug repositioning KW - drug repurposing KW - positive predictive value KW - putrescine uptake KW - virtual screening SP - 173 EP - 173 JF - Frontiers in cellular and infection microbiology JO - Front Cell Infect Microbiol VL - 8 N2 - Chagas disease is a neglected tropical disease endemic to Latin America, though migratory movements have recently spread it to other regions. Here, we have applied a cascade virtual screening campaign combining ligand- and structure-based methods. In order to find novel inhibitors of putrescine uptake in Trypanosoma cruzi, an ensemble of linear ligand-based classifiers obtained by has been applied as initial screening filter, followed by docking into a homology model of the putrescine permease TcPAT12. 1,000 individual linear classifiers were inferred from a balanced dataset. Subsequently, different schemes were tested to combine the individual classifiers: MIN operator, average ranking, average score, average voting, with MIN operator leading to the best performance. The homology model was based on the arginine/agmatine antiporter (AdiC) from Escherichia coli as template. It showed 64% coverage of the entire query sequence and it was selected based on the normalized Discrete Optimized Protein Energy parameter and the GA341 score. The modeled structure had 96% in the allowed area of Ramachandran's plot, and none of the residues located in non-allowed regions were involved in the active site of the transporter. Positivity Predictive Value surfaces were applied to optimize the score thresholds to be used in the ligand-based virtual screening step: for that purpose Positivity Predictive Value was charted as a function of putative yields of active in the range 0.001-0.010 and the Se/Sp ratio. With a focus on drug repositioning opportunities, DrugBank and Sweetlead databases were subjected to screening. Among 8 hits, cinnarizine, a drug frequently prescribed for motion sickness and balance disorder, was tested against T. cruzi epimastigotes and amastigotes, confirming its trypanocidal effects and its inhibitory effects on putrescine uptake. Furthermore, clofazimine, an antibiotic with already proven trypanocidal effects, also displayed inhibitory effects on putrescine uptake. Two other hits, meclizine and butoconazole, also displayed trypanocidal effects (in the case of meclizine, against both epimastigotes and amastigotes), without inhibiting putrescine uptake. SN - 2235-2988 UR - https://www.unboundmedicine.com/medline/citation/29888213/Cascade_Ligand-_and_Structure-Based_Virtual_Screening_to_Identify_New_Trypanocidal_Compounds_Inhibiting_Putrescine_Uptake L2 - https://doi.org/10.3389/fcimb.2018.00173 DB - PRIME DP - Unbound Medicine ER -