Event Information
THE BIOSYNTHESIS OF RHAMNOSE IN SALMONELLA ENTERICA: KINETICS, MOLECULAR DOCKING AND LEAD OPTIMIZATION
- Abstract:
- Ph.D. Defense Examination Seminar
The resurgence of bacterial infections due to antibiotic resistance demands the development of new drugs with novel modes of action. Tuberculosis poses a serious threat as one third of the world’s population is infected and two million die from the disease annually. Rhamnose, a unique deoxyhexose, anchors the exterior layers of Mycobacterial cell walls and has been proven to be an obligatory element for bacterial cell growth. By studying three enzymes responsible for the biosynthesis of rhamnose, we sought to gain greater insight into potential inhibition. RmlB is the first enzyme of interest, and catalyzes the oxidation and reduction of TDP-glucose to 4-keto-6-deoxy-TDP-glucose. Microscopic rate constants were determined for the reaction by stopped flow kinetic data that was modeled to the accepted mechanism previously determined. The rate determining step was proven to be either reduction or product release. The crystal structure of RmlB with substrate analog was then used to develop and run in silico screening of the NCI open database using DOCK5.0. A small number of hits were validated in a coupled assay. A lead molecule was then chosen to test further permutations for increased activity. Overall, the strategies employed demonstrate the obstacles as well as successes that are possible in receptor based drug design.
Student Exams Seminar