Structural investigation of 1,8-dinitro-4,5-dihydroxyanthraquinone and implications for docking as a small molecule inhibitor into the protease of West Nile virus



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Flaviviruses pose a global threat to human health and the development of a broad spectrum drug would decrease the disease burden. The small molecule, 1,8-dinitro-4,5-dihydroxyanthraquinone has shown to bind the proteases of the dengue and West Nile viruses while also reducing their titers in cell-based assays. Structure-based analog design will likely be performed in the near future to increase its activity. However, the binding mechanism and conformation of the lead is unknown. The virtual screen that discovered this inhibitor showed it as having an unorthodox bend in the middle of the anthraquinone structure upon binding the protease. Upon further investigation, tautomerism and a bent configuration may exist in the small molecule. The structure of the small molecule was investigated for structural significance upon binding the dengue and West Nile protease and to see how it affects virtual screening efforts when using AutoDock as the structure-based docking program. It can be concluded that a stable tautomer does not exist in our crystal and that the conformation portrays a slight binding nature which could allude to a bent structure in polar solvents. Co-crystallization of the protease and the small molecule did not produce a crystal capable of solving the structure and virtual screening experiments would be virtually unaffected if the tautomer or bent structure was added to a small molecule database. The tautomer and bent structure may still provide slight differences in the binding affinity upon binding the West Nile NS2B-NS3 protease.