Structure-activity relationships obtained from bioassaying compound collections rapidly provides an understanding of the biological system under study and identifies key structural fragments that are important for biological activity. For example, we have described the preparation of series of substituted-triazanes for use as inhibitors of the LolA protein (involved in lipoprotein processing in bacteria). The SAR obtained from the screening of this collection quickly revealed structural elements important for inhibition and allowed for the development of a simple pharmacophoric model. Furthermore, these compounds represent new antibacterial leads with Gram-negative selectivity.
Concurrently, research has been focused on the development of inhibitors for aminoglycoside antibiotic kinases (APHs). Inhibition of these enzymes prevent chemical inactivation of key antibiotics and, effectively, overcome this resistance modality. The parallel synthesis of a library N1- and C3-substituted-pyrazolo[3,4-d]pyrimidines allowed for the identification of useful inhibitors of APHs while also showing that these compounds adopt a binding orientation that is different from that seen in human kinases. Ultimately, his unique binding modality may be exploited to confer selectivity between related human kinases and bacterial APHs.
L-Glutamine: D-fructose-6-phosphate amidotransferase (GFAT) synthesizes glucosamine-6-phosphate (GlcN6P), and is the first and rate- limiting enzyme in the hexosamine biosynthetic pathway. Type II diabetes patients with secondary diabetic complications have elevated levels of GFAT activity. Potent, specific, cell permeable GFAT inhibitors represent important tools for researchers interested in further elucidating GFAT’s role in diabetic complications. Over the last few years, my group has focused on the identification and optimization of GFAT inhibitors.
This chemical biology approach has been exploited by us to help understand secondary metabolism, enzyme transtition-states and other biologically relevant systems.