INVESTIGATING THE NR2F2 STRUCTURE FOR DRUG REPURPOSING

Abstract

Nuclear receptors (NRs) are transcription factors which play a crucial role in regulating various physiological and developmental processes. Within this superfamily, NR2Fs, also known as Chicken Ovalbumin Upstream Promoter Transcription Factor (COUP-TF), is a family of nuclear orphan receptors, due to the lack of endogenous ligands. The NR2Fs are composed of three members: NR2F1 (COUP-TFI), NR2F2 (COUP-TFII) and NR2F6 (COUP-TFIII). Structurally, the two most important regions, but independently from each other, of NRs are the DNA binding domain (DBD) and ligand binding domain (LBD) which is homologous between all three family members. The variable N-terminal is less conserved, the C-terminal region does not exist in all receptors, and its function is not well understood. Due to their central role in cell growth, they are promising candidates as novel therapeutic targets for cancer therapy [T Sajinovic, G Baier. doi: 10.31083/j.fbl2801013]. In this context, we performed a computational analysis on the X-ray crystal structure of the human NR2F2 ligand binding domain (PDBID: 3CJW) to comprehend the potential hotspot binding sites and predict their druggability. The two identified binding sites (Figure) were then used in a virtual screening protocol, including pharmacophore models and docking studies, of large libraries such as Drugbank, FDA, and commercial libraries for drug repurposing. The results of this investigation will be reported and discussed.