Molecular modelling studies of new potential human DNA polymerase alpha alpha inhibitors
- Author(s)
- Barbara Zdrazil, Anja Schwanke, Birte Schmitz, Monika Schäfer-Korting, Hans-Dieter Höltje
- Abstract
The human polymerase alpha alpha (pol alpha alpha) is a promising target for the therapy of cancer e.g. of the skin. The authors recently built a homology model of the active site of human DNA pol alpha alpha. This 3D model was now used for molecular modelling studies with eight novel analogues of 2-butylanilino-dATP, which is a highly selective nucleoside inhibitor of mammalian pol alpha alpha. Our results suggest that a higher hydrophobicity of a carbohydrate side chain (pointing into a spacious hydrophobic cavity) may enhance the strength of the interaction with the target protein. Moreover, acyclic acyclovir-like derivatives outperformed those with a sugar-moiety, indicating that structural flexibility and higher conformational adaptability has a positive effect on the receptor affinity. Cytotoxicity tests confirmed our theoretical findings. Besides, one of our most promising compounds in the molecular modelling studies revealed high selectivity for the SCC-25 cell line derived from squamous cell carcinoma in man.
- Organisation(s)
- External organisation(s)
- Freie Universität Berlin (FU), Heinrich-Heine-Universität Düsseldorf
- Journal
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Volume
- 26
- Pages
- 270-279
- No. of pages
- 10
- ISSN
- 1475-6366
- DOI
- https://doi.org/10.3109/14756366.2010.503609
- Publication date
- 2011
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301209 Pharmacy
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/molecular-modelling-studies-of-new-potential-human-dna-polymerase-alpha-alpha-inhibitors(fc7dcf65-14b5-45df-9ced-8bacde6f28f3).html