Data di Pubblicazione:
2021
Abstract:
Targeted protein degradation by PROTACs has emerged as a new modality for the knockdown
of a range of proteins, and, more recently, it has become increasingly clear that the PROTAC
chemical space requires characterization through a pool of ad hoc physicochemical descriptors. In
this study, a new database named PROTAC-DB that provides extensive information about PROTACs
and building blocks was used to obtain the 2D chemical structures of about 1600 PROTACs,
60 E3 ligands, 800 linkers, and 202 warheads. For every structure, we calculated a pool of seven
2D descriptors carefully identified as informative for large and flexible structures. For comparison
purposes, the same procedure was applied to a dataset of about 50 bRo5 approved drugs reported in
the literature. Correlation matrices, PCAs, box plots, and other graphical tools were used to define
and understand the chemical space covered by PROTACs and building blocks in relation to other
compounds. Results show that linkers have different properties than E3 ligands and warheads. Polar
descriptors additivity is not respected when passing from building blocks to degraders. Moreover, a
very preliminary analysis based on three PROTACs with high, intermediate, and low permeability
showed how the most permeable compounds seem to occupy a region closer to bRo5 drugs and, thus,
exhibit different properties than impermeable compounds. Finally, a second database, PROTACpedia,
was used to discuss the relevance of physicochemical descriptors on degradation activity.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
chemical space, degrader, 2D physicochemical descriptors, permeability, PROTAC
Elenco autori:
Giuseppe Ermondi, Diego Garcia Jimenez, Giulia Caron
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