Structure based in-silico study for the design of novel Curcumin analogs against Farnesoid-X-receptor (FXR) receptor...

Farnesoid X receptor (FXR) is a multifunctional nuclear receptor that plays an essential role in liver regeneration, maintaining liver homeostasis, counterregulation of hepatic inflammation, and regulation of immune response. As the expression of FXR is downregulated during the development of liver cancer, there may be a loss of function, and hence, designing a novel therapeutic can help overcome this issue. Curcumin, a polyphenol extracted from the rhizome of Curcuma longa L., has multiple, molecular targets which make it a suitable ligand molecule as it acts as an anti-cancer, anti-inflammatory, and antioxidant. Despite its efficacy, it hinders applicability due to its low bioavailability, short half-life, rapid metabolism, and elimination. Curcumin analogs can be designed by incorporating fluoro atoms containing groups as they can improve metabolic stability, better physicochemical properties, and increased binding affinity. The study includes molecular docking of designed curcumin analogs with the FXR receptor (6HL1) and understanding their docking energy, interactions, molecular dynamic simulations, and ADMET properties. From 18 designed analogs, the best docking score was found in the 13d analog, which is - 10.228 kcal/mol. Further molecular dynamic simulation of the 6HL1-13d complex was performed to check its structural stability, and interactions, identifying some common amino acids such as TYR361 and MET265, which are present during both molecular docking and simulations.

The online version contains supplementary material available at 10.1007/s40203-025-00456-9.