Virtual screening for novel inhibitors of Trypanosoma cruzi 6-phosphogluconate dehydrogenase

• In Event: Poster Presentation and Judging for: Biomedical; Cell & Molecular Biology; Chemistry & Biochemistry; Marine Science; Systematics & Evolutionary Biology.
  In Poster Session: Chemistry & Biochemistry Poster Session

Abstract

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects at least 8 million people in Latin America, with 30-40% of those infected developing cardiomyopathy or digestive megasyndromes in their life. Chagas is recognized by the World Health Organization (WHO) as one of 13 neglected tropical diseases, and those with Chagas often go untreated. Current treatments such as benznidazole or nufurtimox do not work well in treating the disease long-term and have significant side effects. In hopes of finding a more suitable and effective drug for the treatment of Chagas disease, virtual drug screening was carried out against the 6-phosphogluconate dehydrogenase (6PGDH) enzyme, an essential part of the pentose phosphate pathway. Structure-based in silico docking was performed on theTi3D drug-discovery high-performance computer. Approximately 27,437 ligands from multiple ligand libraries were assessed against the TC6PGDH enzyme for their predicted binding potential using GOLD molecular docking software. A homology model was created by threading the protein sequence for T. cruzi 6PGDH through the crystal structure for Trypanosoma bruceii 6PGDH (PDB: 1pgj) using ICM. The position of 6-phosphogluconate (6PG) and NADP+ were inferred and used to define the active site of TC6PGDH. At least 10 ligands were found to score higher (87.91-92.21) than the native 6PG (33.16) ligand and follow Lipinski’s rule of 5. In preparation for expression of the enzyme to test against the potential inhibitors found through virtual screening, the coding DNA sequence for TC6PGDH was cloned (putatively) into a PET expression vector for later metal-affinity purification (pNIC-Bsa4).

Author

• Kaan Kumru, University of Texas at Austin