953 research outputs found
New therapeutic modalities in drug discovery and development: Insights & opportunities
Editorial for the special issue "New therapeutic modalities in drug discovery and development: Insights & opportunities
In Silico Tools to Extract the Drug Design Information Content of Degradation Data: The Case of PROTACs Targeting the Androgen Receptor
Proteolysis-Targeting Chimeras (PROTACs) have recently emerged as a promising technology in the drug discovery landscape. Large interest in the degradation of the androgen receptor (AR) as a new anti-prostatic cancer strategy has resulted in several papers focusing on PROTACs against AR. This study explores the potential of a few in silico tools to extract drug design information from AR degradation data in the format often reported in the literature. After setting up a dataset of 92 PROTACs with consistent AR degradation values, we employed the BemisâMurcko method for their classification. The resulting clusters were not informative in terms of structureâdegradation relationship. Subsequently, we performed Degradation Cliff analysis and identified some key aspects conferring a positive contribution to activity, as well as some methodological limits when applying this approach to PROTACs. Linker structure degradation relationships were also investigated. Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors
The Block Relevance (BR) analysis to aid medicinal chemists to determine and interpret lipophilicity
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