Poster abstracts

Poster number 14 submitted by Stephanie Kim

Novel binding site of cyclin A2 and potential inhibitors of cyclin A2-CDK2 complex

Stephanie Kim (Department of Chemistry and Biochemistry, OSU), Michele Alves (Department of Pathology, OSU), Patrick Gygli (Department of Pathology, OSU)

Abstract:
Cyclin A2 is the main mammalian S-phase cyclin and has been shown to have diverse roles in cell cycle regulation and DNA damage response. Thus, identifying small molecule regulators of cyclin A2 activity carries a significant potential to regulate diverse cellular processes in both aging/neurodegeneration and in cancer. No functional modulators of cyclin A2 are known to date. Here, we identified a potential allosteric cyclin A2 ligand binding pocket based on high-resolution structural data. Molecular dynamics simulations were used to generate diverse binding pocket conformations for application of the relaxed complex scheme (1-3). We then used structure-based virtual screening to find potential dual cyclin A2 and CDK2 inhibitors. Based on a consensus score of docked poses from Glide and AutoDock Vina, we identified about 40 promising hit compounds, where all PAINS scaffolds were removed from consideration. A biochemical luminescence assay of cyclin A2-CDK2 function was used for experimental verification and we identified two nanomolar and two micromolar inhibitors that were predicted to target both cyclin A2 and CDK2. The four cyclin A2-CDK2 complex inhibitors are the first reported inhibitors that were specifically designed not to target the cyclin A2-CDK2 protein-protein interface.

References:
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Keywords: cyclin A2, computational drug discovery