Dry selection and wet evaluation for the rational discovery of new anthelmintics
| Autor: | Vicente J. Arán, Yolanda Vera Montenegro, Facundo Pérez-Giménez, Yovani Marrero-Ponce, Yeniel González Castañeda, Froylán Ibarra-Velarde, Ricardo Vivas-Reyes, Huong Le-Thi-Thu, Juan A. Castillo-Garit, Hai Pham-The, Fredy Máximo Vergara, Francisco Torrens |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biophysics Non-stochastic and stochastic atom-based bilinear indices Bilinear interpolation LDA-based QSAR model QuBiLs-MAS module 01 natural sciences Set (abstract data type) 03 medical and health sciences Molecular descriptor Statistics Physical and Theoretical Chemistry Molecular Biology Selection (genetic algorithm) Mathematics Free and open source software Training set TOMOCOMD-CARDD software External validation Anthelmintic activity Atom (order theory) Computational creening Condensed Matter Physics Linear discriminant analysis 0104 chemical sciences Indazole 010404 medicinal & biomolecular chemistry 030104 developmental biology Lead generation |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1362-3028 0026-8976 |
| DOI: | 10.1080/00268976.2017.1296194 |
| Popis: | Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a TOMOCOMD-CARDD (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our ‘in-house’ collections of indole, indazole, quinoxaline and cinnoline derivatives (∼200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an invitro assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered. Yovani Marrero-Ponce acknowledges the support from USFQ with partial finance of project ID5455 |
| Databáze: | OpenAIRE |
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