Investigating the Effect of Dexamethasone on CYP3A4 and Glucocorticoid Receptor by in silico Analysis

Cytochromes are enzymes of the dehydrogenase class with a hemoprotein structure in which the iron in these compounds undergoes oxidation and reduction reactions upon receiving or losing electrons. Quantitatively speaking, CYP3A4 is the most important isoenzyme of cytochrome P450, oxidizing foreign organic molecules such as drugs or toxins to cause them to leave the body. Many drugs and antibiotics can induce or inhibit the activity of cytochrome P450, including dexamethasone. Dexamethasone is a steroidal anti-inflammatory drug used to treat of inflammatory diseases and chronic autoimmunity. This study aimed to investigate the induction effect of dexamethasone in biotransformation pathways by in silico tools. Molegro Virtual Docker software was used to investigate the molecular docking of the enzyme and dexamethasone, which indicated the binding of the drug to the enzyme.  The molecular simulation was performed in Linux with the GROMACS program.  Root-mean-square distance (RMSD), and radius of gyration (Rg), were evaluated. The results were analyzed with Pymol and VMD software, and the obtained curve was plotted with GRACE software. Docking results show that a cluster with a bond energy of -60.81 was the best cluster, and the bond size between ligand and internal atoms was -23.191in the complex. In addition, the amount of bond between the ligand and water for this pose was zero. The stability of the enzyme-ligand complex and the induction effect of dexamethasone on CYP3A4 were indicated by RMSD and RG results. Results of RMSD and RG of CYP3A4 glucocorticoid obtained from the simulation showed the stability of binding of the drug to the enzyme. Also, RMSD results showed the stability of glucocorticoid and dexamethasone complex during molecular dynamics simulation. It reached relative stability at 0.8 nm after 80,000 ps until the end of the simulation.