ArticleCurrent computer-aided drug design2021
Identification of Novel Cyclin A2 Binding Site and Nanomolar Inhibitors of Cyclin A2-CDK2 Complex.
Article in Current computer-aided drug design, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed, 8 citations in OpenAlex.
- Comparative study of the chemical profile, cytotoxic activity, and molecular docking of Serenoa repens extract and a pharmaceutical product.Scientific reports · 2025Article
- Cyclin A2 and Ki-67 proliferation markers could be used to identify tumors with poor prognosis in African American women with breast cancer.Journal of cancer biology · 2023Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundGiven the diverse roles of cyclin A2 both in cell cycle regulation and in DNA damage response, identifying small molecule regulators of cyclin A2 activity carries significant potential to regulate diverse cellular processes in both ageing/neurodegeneration and in cancer.
objectiveBased on cyclin A2's recently discovered role in DNA repair, we hypothesized that small molecule inhibitors that were predicted to bind to both cyclin A2 and CDK2 will be useful as a radiosensitizer of cancer cells. In this study, we used structure-based drug discovery to find inhibitors that target both cyclin A2 and CDK2.
methodsMolecular dynamics simulations were used to generate diverse binding pocket conformations for application of the relaxed complex scheme. 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.
resultsFour lead inhibitors of cyclin A2-CDK2 complex have been identified using a relaxed complex scheme virtual screen have been verified in a biochemical luminescence assay of cyclin A2- CDK2 function. Two of the four lead inhibitors had inhibitory concentrations in the nanomolar range.
conclusionThe 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. Overall, our results highlight the potential of combined advanced computational tools and biochemical verification to discover novel binding scaffolds.
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Registered trials
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