Computational and Experimental Druggability Assessment of Human DNA Glycosylases

Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.

Visnes, Torkild (författare)
Homan, Evert J.Karolinska Institutet (författare)
Seashore-Ludlow, BrintonKarolinska Institutet (författare)
Hedenström, Mattias,1976-Umeå universitet,Kemiska institutionen(Swepub:umu)mashem96 (författare)
Wiita, EliseeKarolinska Institutet (författare)
Vallin, Karl (författare)
Paulin, Cynthia B. J. (författare)
Zhang, Jiaxi (författare)
Wallner, OlovKarolinska Institutet (författare)
Scobie, Martin (författare)
Schmidt, Andreas (författare)
Jenmalm-Jensen, AnnikaKarolinska Institutet (författare)
Berglund, Ulrika WarpmanKarolinska Institutet (författare)
Helleday, ThomasKarolinska Institutet (författare)
Karolinska InstitutetKemiska institutionen (creator_code:org_t)

Av författaren/redakt...: Michel, Maurice; Visnes, Torkild; Homan, Evert J.; Seashore-Ludlow, ...; Hedenström, Matt ...; Wiita, Elisee; visa fler...; Vallin, Karl; Paulin, Cynthia ...; Zhang, Jiaxi; Wallner, Olov; Scobie, Martin; Schmidt, Andreas; Jenmalm-Jensen, ...; Berglund, Ulrika ...; Helleday, Thomas; visa färre...

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