IMHB-Mediated Chameleonicity in Drug Design: A Focus on Structurally Related PROTACs.
J Med Chem
; 67(13): 11421-11434, 2024 Jul 11.
Article
en En
| MEDLINE
| ID: mdl-38943610
ABSTRACT
Molecular chameleonicity may enable compounds to compensate for the unfavorable ADME properties typically associated with complex molecules, such as PROTACs. Here we present a few in silico strategies to implement chameleonicity considerations in drug design. Initially, we identified six structurally related CRBN-based PROTACs targeting BET proteins and experimentally verified whether chameleonicity is needed to obtain an acceptable physicochemical profile. Then, we utilized experimental data to validate our novel computational strategies based on tools crafted to encompass a spectrum of complexities and innovative features. After confirming that the formation of IMHBs is the primary driving factor behind chameleonicity, we initially utilized conformational sampling data to define cChameCS, an IMHB-mediated, simple, and rapid chameleonicity predictor index suitable for early drug discovery. Subsequently, we identified dynamic IMHB patterns relevant to chameleonicity through molecular dynamics simulations. Finally, we proposed a workflow for designing structurally related chameleonic PROTACs of potential application in the lead optimization process.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Simulación de Dinámica Molecular
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Italia