Back to Search
Start Over
Molecular design aided by random forests and synthesis of potent trypanocidal agents as cruzain inhibitors for Chagas disease treatment.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2020 Sep; Vol. 96 (3), pp. 948-960. - Publication Year :
- 2020
-
Abstract
- 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 are Trypanosoma cruzi killers. 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 against T. cruzi. On the other hand, T. cruzi killers 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 on T. cruzi Tulahuen (β-galactosidase) with a pEC <subscript>50</subscript> of 4.9. It is inactive in the host cell line showing a selectivity index (SI = EC <subscript>50</subscript> <superscript>cyto</superscript> /EC <subscript>50</subscript> <superscript>T. cruzi</superscript> ) higher than 50.<br /> (© 2020 John Wiley & Sons A/S.)
- Subjects :
- Animals
Crystallography, X-Ray
Cysteine Endopeptidases
Structure-Activity Relationship
Trypanocidal Agents chemical synthesis
Trypanocidal Agents chemistry
Trypanocidal Agents therapeutic use
Chagas Disease drug therapy
Drug Design
Protozoan Proteins antagonists & inhibitors
Trypanocidal Agents pharmacology
Trypanosoma cruzi drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 96
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 33058457
- Full Text :
- https://doi.org/10.1111/cbdd.13663