Chemical space docking enables large-scale structure-based virtual screening to discover ROCK1 kinase inhibitors.
Nat Commun
; 13(1): 6447, 2022 10 28.
Article
em En
| MEDLINE
| ID: mdl-36307407
ABSTRACT
With the ever-increasing number of synthesis-on-demand compounds for drug lead discovery, there is a great need for efficient search technologies. We present the successful application of a virtual screening method that combines two advances (1) it avoids full library enumeration (2) products are evaluated by molecular docking, leveraging protein structural information. Crucially, these advances enable a structure-based technique that can efficiently explore libraries with billions of molecules and beyond. We apply this method to identify inhibitors of ROCK1 from almost one billion commercially available compounds. Out of 69 purchased compounds, 27 (39%) have Ki values < 10 µM. X-ray structures of two leads confirm their docked poses. This approach to docking scales roughly with the number of reagents that span a chemical space and is therefore multiple orders of magnitude faster than traditional docking.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas
/
Inibidores de Proteínas Quinases
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos