Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment

• Type: Article in International Scientific Journal
• Date: 2020

Authors

de Albuquerque, S (Author) Other; Cianni, L (Author) Other; de Vita, D (Author) Other; Duque, C (Author) Other; Gomes, ASM (Author) Other; Paula Gomes (Author) FCUP; Laughton, C (Author) Other; Leitao, A (Author) Other; Montanari, CA (Author) Other; Montanari, R (Author) Other; Ribeiro, JFR (Author) Other; da Silva, JS (Author) Other; Teixeira, C (Author) Other

Journal

Title: Chemical Biology and Drug Design

Vol. 96

Pages: 948-960

ISSN: 1747-0277

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 1 Citation

Other information

Authenticus ID: P-00S-WG6

DOI: 10.1111/cbdd.13663

Abstract (EN): Cruzain is an established target for the identification of novel trypanocidal agents, but how good are in vitro/in vivo correlations? This work describes the development of a random forests model for the prediction of the bioavailability of cruzain inhibitors that areTrypanosoma cruzikillers. Some common properties that characterize drug-likeness are poorly represented in many established cruzain inhibitors. This correlates with the evidence that many high-affinity cruzain inhibitors are not trypanocidal agents againstT. cruzi. On the other hand,T. cruzikillers that present typical drug-like characteristics are likely to show better trypanocidal action than those without such features. The random forests model was not outperformed by other machine learning methods (such as artificial neural networks and support vector machines), and it was validated with the synthesis of two new trypanocidal agents. Specifically, we report a new lead compound,Neq0565, which was tested onT. cruziTulahuen (beta-galactosidase) with a pEC(50)of 4.9. It is inactive in the host cell line showing a selectivity index (SI = EC50cyto/EC50T. cruzi) higher than 50.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13