Identification of Mechanism of Action and Novel Compounds Targeting HsDHODH: Insights from Computational Analysis

HsDHODH is a target of the human dehydrogenase enzyme, and HsDHODH inhibitors have shown potential applications in treating autoimmune diseases and cancer. Specific inhibitors have demonstrated potential therapeutic efficacy in treating autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. However, the use of HsDHODH inhibitors may cause some side effects, such as interfering with DNA synthesis and causing apoptosis, which can be harmful to the body. In addition, drug resistance may occur during their use. Furthermore, the pharmacological mechanism of action of HsDHODH inhibitors is not fully understood, which may limit their use in treating specific diseases. Recently, the ASGBIE_ESS method was used to calculate the binding free energy between HsDHODH and ascofuranone derivatives. The results showed a correlation of 0.9066 with experimental data, indicating the method's reliability. The energy decomposition analysis identified several hot-spot residues, including M13, L16, Q17, H26, F32, F68, R106, Y326, and T330, that play crucial roles in the ligand-protein binding process based on the crystal structure. Combining virtual screening with the ASGBIE_ESS method, new compounds with unique backbones that have the potential to be valuable inhibitors of HsDHODH were identified. Remarkably, the computational predictions for the biological activity of these derivatives exceeded experimental results. The analysis showed that the identified compounds form stable hydrophobic interactions with residues around the pocket in the protein's hydrophobic region. Additionally, the binding ability of these derivatives is improved when they form hydrogen bonding interactions with specific residues in the pocket. In conclusion, this study provides valuable insights into the mechanism of ligand-protein binding for HsDHODH and offers promising leads for developing novel inhibitors targeting this enzyme.