In Silico Analysis of Saroglitazar and Ferulic Acid Binding to Human Ketohexokinase: Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

BACKGROUND

Non-alcoholic fatty liver disease renamed as metabolic dysfunction-associated steatotic liver disease (MASLD) and a global health issue that causes excessive liver fat deposition without alcohol usage. Basic fatty liver to non-alcoholic steatohepatitis can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Role of research is vital due to the multifaceted, complex pathophysiology and the increasing incidence of a sedentary lifestyle. Computational network pharmacology, docking and dynamics studies of saroglitazar and ferulic acid with human ketohexokinase (KHK) were conducted to propose potential MASLD management.

METHOD

Utilized computational methodologies were utilized to examine binding interactions of saroglitazar (compound identifier (CID): 60151560) and ferulic acid (CID: 445858) with human ketohexokinase (KHK: P50053, Protein Data Bank (PDB) ID: 6W0W). Active site analysis was done by using the Conserved Domain Database (CDD) server (Collaborative Drug Discovery, Burlingame, California) and BIOVIA Discovery Studio 2019 (Dassault Systèmes, Vélizy-Villacoublay, France). The best PDB complex was used for molecular dynamics simulation and trajectory analysis on 100 ns, and functional associations were checked based on network analysis using the Search Tool for Interactions of Chemicals (STITCH) server (STITCH Consortium (EMBL), Heidelberg, Germany).

RESULTS

Human ketohexokinase (KHK) protein (UniProt ID: P50053) was obtained. Additional KHK PDB Structure (6W0W) was retrieved for docking calculation. PubChem Database 2 Structure-Data File (SDF) files (National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine, Bethesda, Maryland), ferulic acid (CID: 445858) and saroglitazar (CID: 60151560) were used as ligands. Active site residues were identified using the CDD server and BIOVIA Discovery Studio 2019. Further, identified active site residues, i.e., Arg, Trp, Glu, Gly, Ala, Pro, Pro, Val, Thr, Gly, Cys, Gly, and Cyswere used as potential active site for docking. D. E. Shaw Research Molecular Dynamics (DESMOND, Schrödinger, Inc., New York) was used for molecular dynamics simulation and trajectory analysis equilibrated after 40 ns in best-docked complex (saroglitazar (CID: 60151560) and KHK; binding energy: -21 kcal/mol).

CONCLUSION

The study shows that saroglitazar and ferulic acid are potent KHK inhibitors for metabolic diseases, including MASLD, suggesting multi-target treatments.