In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily

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Abstract

Background: 

Due to the conserved nature of the poly(ADP-ribose) polymerase (PARP) catalytic domain, the identification of unique residues is critical for the design of selective inhibitors. With inhibitors of the DNA-dependent PARP members already clinically approved, new efforts lie in discovering selective inhibitors for PARP5a and beyond. Targeting the noncatalytic domains, such as the macro2 and WWE domains may also provide a way to achieve selectivity. 

Methodology & results: 

This paper details the in silico profiling of x-ray crystal structures and homology models of the PARP catalytic, WWE and macro2 domains. PARP10 was the least conserved catalytic domain, with the macro2 and WWE domains possessing more unique residues than their catalytic counterparts. 

Conclusion: 

Overall, we identify unique residues to target when designing selective PARP inhibitors including HIS1610, TYR1620, ALA1627 and ARG1658 of the PARP14 catalytic domain, along with multiple unique residues across the PARP WWE and macro2 domains.

Original languageEnglish
Pages (from-to)2105-2122
Number of pages18
JournalFuture Medicinal Chemistry
Volume12
Issue number23
Early online date23 Nov 2020
DOIs
Publication statusPublished - Dec 2020

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