Browsing by Subject "Tautomerism"
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Item 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(2010-03-15) Jeff Allen Borgeson; Marc C. Morais, PhD; Stanley J. Watowich, PhD; Andres F. Oberhauser, PhDFlaviviruses 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.Item Substituent effects on the tautomerization of amino acids(Texas Tech University, 1995-12) Cheung, Eric Tung-LamThe goal of this research is to examine the substituent effects of alkyl groups on the tautomerization of N,N-dimethylamino acids. This study of substituent effects on the tautomeric distribution of zwitterion and neutral unionized tautomer was studied in D2O and CD3CN. The percentage of zwitterion was determined in these solvents for N,Ndimethylglycine, N,N-dimethylalanine, N,N-dimethylvaline, N,Ndimethylleucine, and N,N-dimethylisoleucine. The role of the solvent on the amino acid tautomerization was also investigated. Computational methods were also applied to this study to examine the substituent effects on amino acid tautomerization. Spartan and Gaussian 92 programs were utilized to perform the molecular modeling task (HF/STO-3G, HF/6-311++G**) for the identification of the potential energy minima for the zwitterion model and the neutral unionized tautomer model. The design for models of the zwitterion and the neutral unionized tautomer were also investigated in this study. The relative energy difference in these minima for the zwitterion and the neutral unionized tautomer provides information on the relative stability of the tautomers.