Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity.
Mattia MoriFrancesca GhirgaBeatrice AmatoLuca SeccoDeborah QuaglioIsabella RomeoMarta GambirasiAlberta BergamoSonia CovaceuszachRiccardo SgarraBruno BottaGuidalberto ManfiolettiPublished in: ACS omega (2023)
HMGA proteins are intrinsically disordered (ID) chromatin architectural factors characterized by three DNA binding domains (AT-hooks) that allow them to bind into the DNA minor groove of AT-rich stretches. HMGA are functionally involved in regulating transcription, RNA processing, DNA repair, and chromatin remodeling and dynamics. These proteins are highly expressed and play essential functions during embryonic development. They are almost undetectable in adult tissues but are re-expressed at high levels in all cancers where they are involved in neoplastic transformation and cancer progression. We focused on identifying new small molecules capable of binding into the minor groove of AT-rich DNA sequences that could compete with HMGA for DNA binding and, thus, potentially interfere with their activities. Here, a docking-based virtual screening of a unique high diversity in-house library composed of around 1000 individual natural products identified 16 natural compounds as potential minor groove binders that could inhibit the interaction between HMGA and DNA. To verify the ability of these selected compounds to compete with HMGA proteins, we screened them using electrophoretic mobility shift assays. We identified Sorocein C, a Diels-Alder (D-A)-type adducts, isolated from Sorocea ilicifolia and Sorocea bonplandii with an HMGA/DNA-displacing activity and compared its activity with that of two structurally related compounds, Sorocein A and Sorocein B. All these compounds showed a cytotoxicity effect on cancer cells, suggesting that the Sorocein-structural family may provide new and yet unexplored chemotypes for the development of minor groove binders to be evaluated as anticancer agents.
Keyphrases
- dna binding
- transcription factor
- circulating tumor
- dna repair
- cell free
- dna damage
- single molecule
- gene expression
- nucleic acid
- high throughput
- young adults
- risk assessment
- oxidative stress
- circulating tumor cells
- molecular dynamics
- childhood cancer
- molecular dynamics simulations
- squamous cell carcinoma
- human health
- binding protein
- dna damage response
- single cell
- drug induced