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In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily.
Future Med Chem. 2020 12; 12(23):2105-2122.FM

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Kam CM
Faculty of Health Sciences & Medicine, Bond University, Robina, QLD 4229, Australia.
Tauber AL
Faculty of Health Sciences & Medicine, Bond University, Robina, QLD 4229, Australia.
Oosthuizen DL
Faculty of Health Sciences & Medicine, Bond University, Robina, QLD 4229, Australia.
Levonis SM
Faculty of Health Sciences & Medicine, Bond University, Robina, QLD 4229, Australia.
Schweiker SS
Faculty of Health Sciences & Medicine, Bond University, Robina, QLD 4229, Australia.

MeSH

BiocatalysisHumansModels, MolecularMolecular StructurePoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) Polymerases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33225737

Citation

Kam, Caleb M., et al. "In Silico Family-wide Profiling and 3D Modelling of the poly(ADP-ribose) Polymerase Superfamily." Future Medicinal Chemistry, vol. 12, no. 23, 2020, pp. 2105-2122.
Kam CM, Tauber AL, Oosthuizen DL, et al. In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily. Future Med Chem. 2020;12(23):2105-2122.
Kam, C. M., Tauber, A. L., Oosthuizen, D. L., Levonis, S. M., & Schweiker, S. S. (2020). In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily. Future Medicinal Chemistry, 12(23), 2105-2122. https://doi.org/10.4155/fmc-2020-0274
Kam CM, et al. In Silico Family-wide Profiling and 3D Modelling of the poly(ADP-ribose) Polymerase Superfamily. Future Med Chem. 2020;12(23):2105-2122. PubMed PMID: 33225737.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily. AU - Kam,Caleb M, AU - Tauber,Amanda L, AU - Oosthuizen,Dean L, AU - Levonis,Stephan M, AU - Schweiker,Stephanie S, Y1 - 2020/11/23/ PY - 2020/11/24/pubmed PY - 2021/8/4/medline PY - 2020/11/23/entrez KW - ARTD KW - PARP KW - PARP inhibitors KW - computational chemistry KW - modelling SP - 2105 EP - 2122 JF - Future medicinal chemistry JO - Future Med Chem VL - 12 IS - 23 N2 - 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. SN - 1756-8927 UR - https://www.unboundmedicine.com/medline/citation/33225737/In_silico_family_wide_profiling_and_3D_modelling_of_the_poly_ADP_ribose__polymerase_superfamily_ DB - PRIME DP - Unbound Medicine ER -