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Winfield, KS, United States

Hecht D.,Southwestern College at Winfield | Fogel G.B.,Natural Selection Inc.
Journal of Computer-Aided Molecular Design | Year: 2012

Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development. © 2012 Springer Science+Business Media Dordrecht. Source

Smith D.E.,San Diego State University | Marquez I.,San Diego State University | Lokensgard M.E.,San Diego State University | Rheingold A.L.,University of California at San Diego | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2015

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off-target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure-based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds. Rigidified: A series of conformationally stable kinase inhibitors were synthesized, and the effect of atropisomerism on kinase selectivity was assessed. The use of these inhibitors was found to lead to improved selectivity compared with the rapidly interconverting parent compounds. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Ungar H.,Cabrillo College | Brown D.R.,Southwestern College at Winfield
Journal of Chemical Education | Year: 2010

ChemEd Bridges is an NSF-funded project that provides career and professional development opportunities for chemistry faculty members who teach at two-year colleges (2YCs). We broaden the interests and the horizons of these faculty members by building bridges between them and the broader community of chemical educators. In particular, we have increased the involvement of 2YC faculty in ACS national and regional activities, and we work to strengthen relations between the chemistry faculties of 2YCs and four-year colleges and universities. This report provides an overview of the 2YC student body and faculty, some recent ACS recommendations, and the resources and opportunities that ChemEd Bridges offers. © 2010 The American Chemical Society and Division of Chemical Education, Inc. Source

Hecht D.,Southwestern College at Winfield | Fogel G.B.,Natural Selection Inc.
2012 IEEE Symposium on Computational Intelligence and Computational Biology, CIBCB 2012 | Year: 2012

The evolution of drug resistance in malaria continues to be a widespread concern. Many of these drugs target key proteins such as dihydrofolate reductase (DHFR). However in malaria, the structural plasticity of DHFR allows it to maintain its active site and catalytic activity, while resisting drug binding. One way to better understand this process is through the appreciation of DHFR structural evolution in general, and then use in silico evolution to model both the drug docking and the likely amino acid changes in DHFR that will occur as a result. Using a comprehensive phylogenetic analysis of DHFR, we have generated a method that generates variant DHFR proteins and sequentially scores the docking of the natural cofactor NADPH and the known anti-malarial drug pyrimethamine in order to determine fitness. Iteration of this process allows the opportunity to model the coevolutionary processes involved with drug resistance and to predict responses to pharmaceuticals in advance of their use in the field. © 2012 IEEE. Source

Tsuey-Ching Y.,National Yang Ming University | Hecht D.,Southwestern College at Winfield | Hecht D.,Asia University, Taiwan | Tsai J.J.P.,Asia University, Taiwan | And 2 more authors.
Research in Microbiology | Year: 2012

In Xanthomonas campestris pv. campestris (Xcc), the chromosomally encoded class A β-lactamase (Blaxcc) is expressed at a high basal level in the absence of an inducer and its expression is inducible by ampicillin. Like most of the class A β-lactamases, Blaxcc cannot digest the β-lactam ring of cefoxitin. However, Xcc exhibits high basal resistance to cefoxitin. A promoter activity assay with Pblaxcc-lacZ transcriptional fusion from a plasmid and western blotting using anti-Blaxcc polyclonal antibodies demonstrated that a sublethal concentration of cefoxitin can induce expression of the blaxcc gene. Cefoxitin can be used as an inducer to study blaxcc expression in blaxcc-deficient mutants such as Xcbla and XcampR. Addition of cefoxitin to the Bla enzyme solution blocks β-lactamase activity, suggesting that cefoxitin is an inhibitor of Blaxcc. This explains why there is no β-lactamase activity in cefoxitin-induced Xcc. A significant synergistic effect was also observed between cefoxitin and other β-lactam antibiotics. A homology model demonstrated that the methoxy-group in the β-lactam ring of cefoxitin tends to displace the conserved catalytic water molecule into the active cavity of Blaxcc, thus leading to formation of a stable but inactive acyl-Blaxcc intermediate. © 2012 Institut Pasteur. Source

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