DegraderTCM: A Computationally Sparing Approach for Predicting Ternary Degradation Complexes.
ACS Med Chem Lett
; 15(1): 45-53, 2024 Jan 11.
Article
em En
| MEDLINE
| ID: mdl-38229751
ABSTRACT
Proteolysis targeting chimeras (PROTACs or degraders) represent a novel therapeutic modality that has raised interest thanks to promising results and currently undergoing clinical testing. PROTACs induce the selective proteasomal degradation of undesired proteins by the formation of ternary complexes (TCs). Having knowledge of the 3D structure of TCs is crucial for the design of PROTAC drugs. Here, we describe DegraderTCM, a new computational method for modeling PROTAC-mediated TCs that requires low computational power and provides sound results in a short time span. We validated DegraderTCM against a selected set of experimentally determined structures and defined a method to predict the PROTAC degradation activity based on the computed TC structure. Finally, we modeled TCs of known degraders holding significance for defining the method's applicability domain. A retrospective analysis of structure-activity relationships unveiled possibilities for utilizing DegraderTCM in the initial stages of designing novel PROTAC drugs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
ACS Med Chem Lett
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Itália