{
  "abstract": "Introduction NFY is a transcription factor complex of three subunits (NFYA, NFYB and NFYC), which specifically binds to CCAAT sequences in the promoters of genes involved in cell proliferation, metabolism and collagen expression. NFY has recently been implicated in the response to cardiac injury, promoting cardiac fibrosis and cardiac fibroblast proliferation.Methods We used the Bristol University Docking Engine (BUDE) software to perform in silico molecular docking of the NFYB:NFYC dimer with a database of 8 million drug-like compounds, in an attempt to identify novel small molecule inhibitors of NFY-function. We targeted a small pocket on NFYB, which is normally occupied by the side-chain of the highly cross-species conserved Arginine 295 of NFYA. We hypothesised that this residue would have an important function in regulating the positioning of the NFYA DNA binding domain.Results BUDE ranked all 8 million compounds of the drug-like subset of the ZINC8-database by free binding energy. Six of the best scoring commercially available compounds were tested for NFY-inhibitory properties using cardiac fibroblasts transfected with a reporter gene under the control of a synthetic promoter containing five NFY binding elements. One of these compounds (referred to as NFYi-5) significantly inhibited NFY-reporter gene activity, without affecting cell viability or inhibiting the activity of non-NFY-dependent promoters (e.g. CMV, UBC, synthetic NF-kB). Furthermore, NFYi5 repressed the mRNA levels of NFY-dependent genes (CCNA2, CCNB1, ECT2 and DDX11) but not levels of housekeeper genes (TBP, 36B4, GAPDH, UBC). Moreover, treatment of cells with 20 uM NFYi5 significantly reduced cardiac fibroblast proliferation, measured by EDU incorporation and total cell number. EMSA analysis indicates that NFYi5 inhibits DNA binding of NFY-subunits to DNA.Conclusion Taken together, our data indicates that NFYi-5 represents a novel and specific NFY inhibitor with anti-mitogenic properties. This compound may represent a valuable lead compound for the development of NFY-targeting therapies for the treatment of cardiac fibrosis.",
  "authors": [
    {
      "affiliations": [
        "University of Bristol, Bristol, UK"
      ],
      "name": "Mark Bond"
    },
    {
      "affiliations": [
        "University of Bristol, Bristol, UK"
      ],
      "name": "Reza Ebrahimighaei"
    },
    {
      "affiliations": [
        "University of Bristol, Bristol, UK"
      ],
      "name": "Jon Lees"
    }
  ],
  "title": "BS08 Identification of a novel pharmacological inhibitor of NFY transcription factor using in silico molecular docking, which inhibits cariac fibroblast proliferation",
  "uid": "fe77d2e8-0031-56c9-a822-9db9ea872ce0"
}