Dark chemical matter as a promising starting point for drug lead discovery.
Nat Chem Biol
; 11(12): 958-66, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26479441
ABSTRACT
High-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Cryptococcus neoformans
/
Descoberta de Drogas
/
Ensaios de Triagem em Larga Escala
/
Antifúngicos
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos