BBB seminar: Bjørn Dalhus
Identification of inhibitors of human OGG1 DNA glycosylase
Department of Medical Biochemistry, Institute for Clinical Medicine, University of Oslo
Reactive oxygen species cause oxidative damage to DNA; e.g. the oxidation of guanine, generating the mutagenic residue 8-oxoguanine. The primary enzyme for removal of 8oxoG in human cells is OGG1, which initiates the base excision repair (BER) pathway by flipping the 8oxoG base into a lesion specific pocket, followed by base removal by hydrolysis. Ionizing radiation and selected anti-tumor agents used to treat cancer exert their toxicity by inducing DNA damage. In this respect, DNA repair enzymes like OGG1 have the potential to work as resistance factors, reducing the effect of current therapies. Thus, DNA glycosylases form an interesting class of cancer drug adjuvant targets.
We have used two separate approaches for the primary screening of OGG1; computational screening against a virtual library, and protein thermal shift assay against a library of 10,000 compounds. Based on these primary screenings, compounds were selected for crystallographic screening, comprising both soaking and co-crystallization experiments.
We have obtained experimental structures of human OGG1 in complex with a series of novel ligands. The ligands all bound in the active DNA-binding site, and were further confirmed as inhibitors of OGG1. These hits could serve as scaffolds for the development of potent OGG1 inhibitors.
Chairperson: Aurora Martinez <firstname.lastname@example.org>, Department of Biomedicine