Analysis of Functional Promoter of Camel FGF21 Gene and Identification of Small Compounds Targeting FGF21 Protein

Simple Summary The fibroblast growth factor 21 (FGF21) gene plays an important role in the mechanism of glucose and lipid metabolism and is a promising therapeutic target for metabolic disease. Camel displayed a unique regulation characteristic of glucose and lipid metabolism, endowing them with the ability to adapt to survive under drought and chronic hunger. However, the knowledge about the camel FGF21 gene regulation and its differences between humans and mice is still limited. This study obtained the camel FGF21 promoter sequence, determined its core active regions and specific regulatory pattern different from humans and mice, and further screened two potential small molecules targeting FGF21 protein using molecular docking and in silico ADMET druggability prediction. This study expanded the functions of these small molecules and provided a foundation for drug development targeting FGF21. The fibroblast growth factor 21 (FGF21) gene plays an important role in the mechanism of glucose and lipid metabolism and is a promising therapeutic target for metabolic disease. Camels display a unique regulation characteristic of glucose and lipid metabolism, endowing them with the ability to adapt to survive drought and chronic hunger. However, the knowledge about the camel FGF21 gene regulation and its differences between humans and mice is still limited. In this study, camel FGF21 gene promoter was obtained for similar to 2000 bp upstream of the transcriptional start site (TSS). Bioinformatics analysis showed that the proximal promoter region sequences near the TSS between humans and camels have high similarity. Two potential core active regions are located in the -445-612 bp region. In addition, camel FGF21 promoter contains three CpG islands (CGIs), located in the -435 similar to-1168 bp regions, significantly more and longer than in humans and mice. The transcription factor binding prediction showed that most transcription factors, including major functional transcription factors, are the same in different species although the binding site positions in the promoter are different. These results indicated that the signaling pathways involved in FGF21 gene transcription regulation are conservative in mammals. Truncated fragments recombinant vectors and luciferase reporter assay determined that camel FGF21 core promoter is located within the 800 bp region upstream of the TSS and an enhancer may exist between the -1000 and -2000 bp region. Combining molecular docking and in silico ADMET druggability prediction, two compounds were screened as the most promising candidate drugs specifically targeting FGF21. This study expanded the functions of these small molecules and provided a foundation for drug development targeting FGF21.

Automated summary

The FGF21 gene is crucial in glucose and lipid metabolism and is a promising therapeutic target for metabolic diseases. Camels have unique regulation characteristics in glucose and lipid metabolism, which allow them to survive in drought and chronic hunger. This study obtained the camel FGF21 promoter sequence, identified its specific regulatory pattern different from humans and mice, and screened small molecules targeting FGF21 using molecular docking and in silico ADMET druggability prediction. This study expanded the functions of these small molecules and provided a foundation for drug development targeting FGF21.