1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is an enzyme with no human homolog that is essential to the non-mevalonate pathway of isoprenoid synthesis within the bacterium Wolbachia. Inhibition of DXR is a new approach to treating the debilitating condition Lymphatic filariasis, a neglected tropical disease that affects over a billion people worldwide. It is transmitted by mosquitoes and caused by the infectious nematode Brugia malayi and its bacterial endosymbiont Wolbachia. The WbmDXR gene was assembled through PCR amplification of gene fragments and was cloned into the pNIC-Bsa4 expression vector. BL21(DE3) cells were subsequently transformed with the gene product. Protein expression of WbmDXR is currently under way in order to perform in vitro testing of potential inhibitors identified from virtual drug screening methods. Because a virtual structure does not currently exist in scientific literature, a homology model for WbmDXR was created in ICM by using DXR from Zymonas mobilis (PDB: 1r0l) as a template. The model was screened virtually in GOLD against two small-molecule libraries for the discovery of inhibitors, and three potential drug compounds were selected. WbmDXR is a novel drug target and this research provides a new way of treating Lymphatic filariasis as well as creates opportunity for further study of this pathway in Wolbachia.Figure 1. Compound 6322987, the highest ranking potential inhibitor from the CBKin Library, docked within the active site of WbmDXR. The GOLD fitness score was 74.96.

1-deoxy-D-xylulose 5-phosphate reductoisomerase in Wolbachia endosymbiont Brugia malayi researched as novel drug target for lymphatic filariasis

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.