Nasrin Amiri-Dashatan1, Mostafa Rezaei-Tavirani1, Mohammad Mehdi Ranjbar2, Mehdi Koushki3, Seyed Dawood Mousavi Nasab4, Nayebali Ahmadi1,5. 1. Shahid Beheshti University of Medical Sciences, Faculty of Paramedical Sciences, Proteomics Research Center, Tehran, Iran. 2. Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran. 3. Zanjan University of Medical Sciences School of Medicine, Department of Clinical Biochemistry, Zanjan, Iran. 4. Pasteur Institute of Iran, Production and Research Complex, Department of Research and Development, Tehran, Iran. 5. Shahid Beheshti University of Medical Sciences, Faculty of Paramedical Sciences, Department of Medical Lab Technology, Tehran, Iran.
Abstract
OBJECTIVES: Leishmaniasis is one of the common forms of neglected parasitic diseases that cause a worldwide disease burden without any effective therapeutic strategy. Control of the disease currently relies on chemotherapy because most of the available drugs have toxic side-effects and drug-resistant strains have emerged. Therefore, the development of new therapeutic strategies to treat patients for leishmaniasis has become a priority. The first step in drug discovery is to identify an effective drug target by methods such as system biology. Protein kinases are a promising drug target for different diseases. Due to lack of a functional krebs cycle in Leishmania species, they use glycolysis as the only source of ATP generation. Pyruvate kinase is the enzyme involved in the last step of glycolysis and considered as essential enzyme for the Leishmania survival. MATERIALS AND METHODS: This study sought to discover FDA approved compounds against the leishmanial pyruvate kinase protein. Our approach involved using quantitative proteomics, protein interaction networks and docking to detect new drug targets and potent inhibitors. RESULTS: Pyruvate kinase was determined as the potential drug target based on protein network analysis. The docking studies suggested trametinib and irinotecan with high binding energies of -10.4 and -10.3 kcal/mol, respectively, as the potential chemotherapeutic agents against L. major. CONCLUSION: This study demonstrated the importance of integrating protein network analysis and molecular docking to identify new anti-leishmanial drugs. These potential inhibitors constitute novel drug candidates that should be tested in vitro and in vivo to determine their potential as an alternative chemotherapy in the treatment of leishmaniasis.
OBJECTIVES: Leishmaniasis is one of the common forms of neglected parasitic diseases that cause a worldwide disease burden without any effective therapeutic strategy. Control of the disease currently relies on chemotherapy because most of the available drugs have toxic side-effects and drug-resistant strains have emerged. Therefore, the development of new therapeutic strategies to treat patients for leishmaniasis has become a priority. The first step in drug discovery is to identify an effective drug target by methods such as system biology. Protein kinases are a promising drug target for different diseases. Due to lack of a functional krebs cycle in Leishmania species, they use glycolysis as the only source of ATP generation. Pyruvate kinase is the enzyme involved in the last step of glycolysis and considered as essential enzyme for the Leishmania survival. MATERIALS AND METHODS: This study sought to discover FDA approved compounds against the leishmanial pyruvate kinase protein. Our approach involved using quantitative proteomics, protein interaction networks and docking to detect new drug targets and potent inhibitors. RESULTS: Pyruvate kinase was determined as the potential drug target based on protein network analysis. The docking studies suggested trametinib and irinotecan with high binding energies of -10.4 and -10.3 kcal/mol, respectively, as the potential chemotherapeutic agents against L. major. CONCLUSION: This study demonstrated the importance of integrating protein network analysis and molecular docking to identify new anti-leishmanial drugs. These potential inhibitors constitute novel drug candidates that should be tested in vitro and in vivo to determine their potential as an alternative chemotherapy in the treatment of leishmaniasis.
Entities:
Keywords:
Leishmania major; docking; drug target; protein network; pyruvate kinase