(813.2) Applying Virtual Screening for Discovery of Novel Inhibitors of Wolbachia Endosymbiont of Brugia malayi Enoyl-Acyl Carrier Protein Reductase (FabI)

Poster Board Number: A365

Annmarie Chang (University of Texas at Austin), Josh Beckham (University of Texas at Austin)

Lymphatic filariasis, more commonly known as elephantiasis, is a tropical parasitic disease caused by nematodes. The parasite infects the lymph nodes, and the disease is endemic in 80 countries, affecting hundreds of millions of people worldwide. A potential target for lymphatic filariasis is the enoyl-(acyl-carrier-protein) reductase (FabI) protein of the Wolbachia endosymbiont of Brugia malayi, a filarial nematode. FabI is a significant, and relatively underutilized, drug target due to its essential role in catalyzing the last step of fatty acid elongation in the bacterial fatty acid biosynthesis pathway. The antiparasitic drug diethylcarbamazine is currently used to treat lymphatic filariasis; however, there are no known antibiotics specifically targeting FabI in the Wolbachia endosymbiont of Brugia malayi, necessitating a search for novel inhibitors of this target using virtual screening. Given that there is no published crystal structure of Wolbachia FabI in the Protein Data Bank (PDB), a 3D homology model was created for molecular docking purposes from 3K2E, an enoyl-(acyl-carrier-protein) reductase from Anaplasma phagocytophilum. A pairwise alignment of both sequences resulted in 65% identity match. Using the molecular docking program Genetic Optimization for Ligand Docking (GOLD), which utilizes a genetic algorithm for ranking, several libraries of compounds were virtually screened against the Wolbachia FabI protein and assigned a fitness score of predicted binding affinity based on binding interactions and conformations. Control ligands were GOLD docked first, resulting in a range of scores from 46.09 to 93.24. Tens of thousands of compounds were then screened from libraries including HitFinder9 and Zinc ChemBridge. The top 10% scoring compounds were screened a second time, and the resulting top 10% were saved; ultimately, the top 1% scoring compounds were analyzed. HitFinder9 and Zinc ChemBridge yielded similar results, with top 1% score ranges of 74.45 to 107.63 and 73.63 to 105.16, respectively. Neither library significantly exceeded the other in terms of high scoring compounds. Top chemical compounds from each library can be investigated further for inhibitory activity of Wolbachia FabI in enzyme assays to determine potential viability as novel inhibitors.