QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites.
ACS Infect Dis
; 8(1): 106-117, 2022 01 14.
Article
em En
| MEDLINE
| ID: mdl-34985259
ABSTRACT
Malaria, caused by Plasmodium parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets. Here, we describe quantitative structure-activity relationship models to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors. The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic acid and were subject to internal and external validation. When used to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial activity, model A7 (external accuracy 91%) identified three hits that were subsequently verified as having potent in vitro activity against P. falciparum parasites (IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity for P. falciparum versus human cells.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Parasitos
/
Malária
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Infect Dis
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Austrália