Exploring protein hotspots by optimized fragment pharmacophores.
Nat Commun
; 12(1): 3201, 2021 05 27.
Article
em En
| MEDLINE
| ID: mdl-34045440
ABSTRACT
Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Histona-Lisina N-Metiltransferase
/
Descoberta de Drogas
/
Ensaios de Triagem em Larga Escala
/
Desenvolvimento de Medicamentos
/
Proteases 3C de Coronavírus
/
Proteases Semelhantes à Papaína de Coronavírus
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Hungria