Abstract
In order to understand the binding modes of human DNA polymerase α (pol α) inhibitors on a molecular level, a 3D homology model of the active site of the enzyme was proposed based on the application of molecular modelling methods and molecular dynamic simulations using available crystal coordinates of pol α relatives. Docking results for a series of known nucleotide analogue inhibitors were consistent with reported experimental binding data and offered the possibility to elucidate structure-activity relationships via investigations of active site-inhibitor interactions. Furthermore, the study could explain, at least partially, the inhibitory effect of aphidicolin on pol α. In molecular dynamics simulations, aphidicolin occupied the catalytic centre, but acted in a not truly competitive manner with respect to nucleotides. It destabilized the replicating “closed” form of the pol α and transferred the enzyme into the inactive “open” conformation. This result is consistent with recent experiments on the binding mode of aphidicolin.
Acknowledgements
This work was financially supported by RIEMSER Arzneimittel AG, Greifswald - Insel Riems, Germany.