N-(5-Chloro-2,4-dihydroxyphenyl)-1-phenylcyclobutanecarboxamide (N-CDPCB, 1a) is found to be an inhibitor of the fat mass and obesity associated protein (FTO). The crystal structure of human FTO with 1a reveals a novel binding site for the FTO inhibitor and defines the molecular basis for recognition by FTO of the inhibitor. The identification of the new binding site offers new opportunities for further development of selective and potent inhibitors of FTO, which is expected to provide information concerning novel therapeutic targets for treatment of obesity or obesity-associated diseases.
The fat mass and obesity-associated protein (FTO), as an mA demethylase, is involved in many human diseases. Virtual screening and similarity search in combination with bioactivity assay lead to the identification of the natural compound radicicol as a potent FTO inhibitor, which exhibits a dose-dependent inhibition of FTO demethylation activity with an IC value of 16.04 μM. Further ITC experiments show that the binding between radicicol and FTO was mainly entropy-driven. Crystal structure analysis reveals that radicicol adopts an L-shaped conformation in the FTO binding site and occupies the same position as N-CDPCB, a previously identified small molecular inhibitor of FTO. Unexpectedly, however, the 1,3-diol group conserved in radicicol and N-CDPCB assumes strikingly different orientations for interaction with FTO. The identification of radicicol as an FTO inhibitor and revelation of its recognition mechanism not only opens the possibility of developing new therapeutic strategies for treatment of leukemia but also provide clues for elucidation of the acting mechanisms of radicicol, which is a possible clinical candidate worth in-depth study.
The origin of the positive temperature effect in fluorescence emission of an ewly designed perylene bisimide (PBI) derivative with two naphthyl units containing orthomethoxy group (NM) at its bay positions (PBI-2NM) was elucidated. Akey point is the finding of aweak hydrogen bond (< 5.0 kcal mol À1 )b etween the methoxy group of the NM unit and anearby hydrogen atom of the PBI core.Itisthe bonding that drives co-planarization of the different aromatic units, resulting in delocalization of the p-electrons of the compound as synthesized,i nducing fluorescence quenching via intramolecular charge transfer (ICT). With increasing temperature, the co-planar structure could be distorted in part, resulting in ad ecreased degree of ICT,a nd hence leading to enhanced fluorescence emission. The unique positive temperature effect in emission induced by H-bond-driven co-planarization may pave an ew avenue in designing functional molecular systems complementary to conventional methods.
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