Pepsin is an aspartic protease that is involved in the digestion of food in the stomach of mammals. Continuous and long-term use of therapeutic agents will cause chronic contact of the drug with pepsin, and as a result, the structure and function of enzyme may change. In this regard the interactions of isoniazid and rifampin as the first line treatments of tuberculosis with pepsin were investigated by various methods such as fluorescence spectroscopy, FTIR, molecular docking and molecular dynamics simulation. Based on the results obtained in this study, the mentioned drugs can form stable complexes with pepsin and the structure of protein changes slightly. According to the results, the major forces in the formation of the protein-drug complex are electrostatic and hydrophobic forces for isoniazid and rifampin respectively and isoniazid shows to form a stronger binding with protein. The FTIR spectrum of the protein shows that little change was occurred in the structure of pepsin in the presence of the drugs. Molecular modeling results of the binding of isoniazid and rifampin to the pepsin confirm laboratory results and show that the binding site of drugs is close to the active site of the enzyme. Also, the activity of pepsin in the presence of both drugs has significantly increased.
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