Elucidation of intermolecular interactions between chlorogenic acid and glucose-6-phosphate translocase: A step...

Glucose-6-phosphate translocase enzyme, encoded by SLC37A4 gene, is a crucial enzyme involved in transporting glucose-6-phosphate into the endoplasmic reticulum. Inhibition of this enzyme can cause Von-Gierke's/glycogen storage disease sub-type 1b. The current study dealt to elucidate the intermolecular interactions to assess the inhibitory activity of Chlorogenic acid (CGA) against SLC37A4 was assessed by molecular docking and dynamic simulation. The alpha folded model of SLC37A4 and CGA 3D structure were optimized using CHARMM force field, using energy minimization protocol in the Discovery Studio software. Glucose-6-phosphate (G6P) and CGA molecular docking, Molecular dynamics (MD) simulation, analysis of binding free energy of G6P-SLC37A4 and CGA-SLC37A4 complexes was performed for 100 ns using GROMACS, followed by principal component analysis (PCA). The docking score of the CGA-SLC37A4 complex exhibited a higher docking score (- 8.2 kcal/mol) when compared to the G6P-SLC37A4 complex (- 6.5 kcal/mol), suggesting a stronger binding interaction between CGA and SLC37A4. Further, the MD simulation demonstrated a stable backbone and complex Root Mean Square Deviation (RMSD), the least RMS fluctuation, and stable active site residue interactions throughout the 100 ns production run. The CGA complex with SLC37A4 exhibits higher compactness and formed 8 hydrogen bonds to achieve stability. The binding free energy of the G6P-SLC37A4 and CGA-SLC37A4 complex was found to be - 12.73 and - 31.493 kcal/mol. Lys29 formed stable contact for both G6P (- 4.73 kJ/mol) and SLC37A4 (- 2.18 kJ/mol). This study imparts structural insights into the competitive inhibition of SLC37A4 by CGA. CGA shows potential as a candidate to induce manifestations of GSD1b by inhibiting glycogenolysis, and gluconeogenesis.

The online version contains supplementary material available at 10.1007/s13205-023-03661-5.