Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake
| Autor: | Juan Francisco Morales, Agustina María Pino Martínez, María Daniela Ruiz, Lucas Nicolás Alberca, Pablo Hernán Palestro, María Laura Sbaraglini, Catalina D. Alba Soto, Roque Carlos Dietrich, Alan Talevi, Laura Virginia Fraccaroli, Carolina Carrillo, Cristian Gabriel Miranda |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Chagas disease Biología Drug Evaluation Preclinical lcsh:QR1-502 Drug repurposing Clofazimine DRUG REPOSITIONING 01 natural sciences lcsh:Microbiology purl.org/becyt/ford/1 [https] chemistry.chemical_compound VIRTUAL SCREENING Original Research biology Imidazoles Ciencias Químicas Trypanocidal Agents Molecular Docking Simulation Infectious Diseases Discrete optimized protein energy DRUG REPURPOSING Biochemistry Agmatine CIENCIAS NATURALES Y EXACTAS Virtual screening Microbiology (medical) Positive predictive value Medicina Trypanosoma cruzi POSITIVE PREDICTIVE VALUE Immunology CINNARIZINE Molecular Dynamics Simulation Microbiology Cinnarizine Putrescine uptake Meclizine 03 medical and health sciences PUTRESCINE UPTAKE Putrescine purl.org/becyt/ford/1.4 [https] Homology modeling Ciencias Exactas Otras Ciencias Químicas CHAGAS DISEASE Drug repositioning Membrane Transport Proteins Biological Transport TRYPANOSOMA CRUZI biology.organism_classification 0104 chemical sciences 010404 medicinal & biomolecular chemistry 030104 developmental biology chemistry Docking (molecular) DrugBank |
| Zdroj: | Frontiers in Cellular and Infection Microbiology, Vol 8 (2018) CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Frontiers in Cellular and Infection Microbiology SEDICI (UNLP) Universidad Nacional de La Plata instacron:UNLP |
| ISSN: | 2235-2988 |
| DOI: | 10.3389/fcimb.2018.00173 |
| Popis: | 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. Facultad de Ciencias Exactas Laboratorio de Investigación y Desarrollo de Bioactivos |
| Databáze: | OpenAIRE |
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