title: Elaboration of a fragment library hit produces potent and selective aspartate semialdehyde dehydrogenase inhibitors.
abstract: Aspartate-β-semialdehyde dehydrogenase (ASADH) lies at the first branch point in the aspartate metabolic pathway which leads to the biosynthesis of several essential amino acids and some important metabolites. This pathway is crucial for many metabolic processes in plants and microbes like bacteria and fungi, but is absent in mammals. Therefore, the key microbial enzymes involved in this pathway are attractive potential targets for development of new antibiotics with novel modes of action. The ASADH enzyme family shares the same substrate binding and active site catalytic groups; however, the enzymes from representative bacterial and fungal species show different inhibition patterns when previously screened against low molecular weight inhibitors identified from fragment library screening. In the present study several approaches, including fragment based drug discovery (FBDD), inhibitor docking, kinetic, and structure-activity relationship (SAR) studies have been used to guide ASADH inhibitor development. Elaboration of a core structure identified by FBDD has led to the synthesis of low micromolar inhibitors of the target enzyme, with high selectivity introduced between the Gram-negative and Gram-positive orthologs of ASADH. This new set of structures open a novel direction for the development of inhibitors against this validated drug-target enzyme.
authors.affiliation: Department of Chemistry & Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Bharani
authors.initials: B
authors.lastname: Thangavelu
authors.affiliation: Department of Chemistry & Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Pravin
authors.initials: P
authors.lastname: Bhansali
authors.affiliation: Department of Chemistry & Biochemistry, University of Toledo, Toledo, OH 43606, USA. Electronic address: ron.viola@utoledo.edu.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Viola
mesh_terms: D001223:Aspartate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D015394:Molecular Structure; D013296:Streptococcus pneumoniae / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D001223:Aspartate-Semialdehyde Dehydrogenase
keywords: Aspartate semialdehyde dehydrogenase; Enzyme inhibitors; Fragment based drug discovery; Structure–activity relationships