The University of Texas at Austin, Texas, United States
Alia Segura (The University of Texas at Austin)| Josh Beckham (The University of Texas at Austin)
The erythrocytic infection and onset of malaria is a result of the protozoan parasitism from the Plasmodium genus. In 2018, there were an estimated 228 million cases of malaria worldwide largely attributed to P. falciparum and P. vivax infections. Current chemotherapy efforts against the Plasmodium parasites target mitochondrial function (Malarone), the 30s ribosomal subunit (Vibramycin) and prevention of the parasite’s abilities to degrade the host’s hemoglobin (Chloroquine), however, rising mutations have decreased their therapeutic effects. The essentiality of 6-phosphogluconate dehydrogenase (6PGDH) is demonstrated in its oxidation of 6-phosphogluconate (6PG) to ribulose-5-phosphate and the reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to provide precursors in nucleic acid synthesis. Here, the homologous 3D structure of 6PGDH from P. falciparum was used for molecular docking studies since there is not a published structure of P. vivax 6PGDH in the Protein Data Bank (PDB). The structures of 6PGDH from P. falciparum and P. vivax display 80.30% sequence identity. The apo form of Pf6PGDH (PDB ID: 6FQX) was aligned with the structures containing the 6PG substrate (PDB ID: 6FQZ) and NADP+ coenzyme (PDB ID: 6FQY) ligands in order to define the active site. The 6PGDH protein was virtually screened against 307,735 ligands from several diverse compound libraries using the molecular docking program Genetic Optimization Ligand Docking (GOLD) and ranked for their predicted binding fitness based on empirical scoring functions of the employed genetic algorithm. The highest binding compound, ZINC55224876, received a GOLD Fitness score of 91.1 and demonstrated strong hydrophobic interactions as quantified by the piecewise linear potential (PLP) sub-score. The ligands gathered to act as controls were obtained from studies conducted on Trypanosoma brucei 6PGDH that demonstrated a reduction in protein function to act as positive controls. The screening of the positive and negative control ligands against the Pf6PGDH structure culminated in GOLD Fitness scores of 74.76 for the highest to the lowest score of 41.75. The top 10% of the highest overall scoring library, the Zinc ChemBridge library (124,345 ligands) resulted in a range of GOLD Fitness scores from 91.1- 59.73, whereas the lowest overall scoring library, Fragment (3,963 ligands) received scores ranging from 59.84-20.88. The resulting top scoring ligands may further be used for future enzyme assays in the process of drug discovery.