Synthesis of Bisubstrate Analog Inhibitors against Aspartate Semialdehyde Dehydrogenase
Aspartate semialdehyde dehydrogenase (ASADH) is an essential enzyme found in bacteria, fungi and plants. This enzyme is responsible for the production of several essential amino acids, and its absence in humans makes ASADH an attractive target for the development of antibiotics. The goal of the project is to design, synthesize and build species-selectivity into bisubstrate analogue inhibitors against ASADH. Analogues were choosen to synthesize based on the docking model predictions for binding affinities and selectivities against ASADHs that have been purified and characterized from different microbial species. The synthetic approach involves the parallel synthesis of secondary amine derivatives and phenyl alkyl halides. The two synthons are being coupled through nucleophilic substitution followed by hydrolysis to form the desired bisubstrate analogues. Four compounds were identified based on docking score and selectivity analyses. These analogs were synthesized and tested against ASADH. These studies have led to identification of sub-millimolar inhibitors of ASADH.This work is supported by a grant from the NIH (AI077720).
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