In silico optimization of a fragment-based hit yields biologically active, high-efficiency inhibitors for glutamate racemase.
A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase (GR), was optimized for both ligand efficiency and lipophilic efficiency. A previously developed hybrid molecular dynamics-docking and scoring scheme, FERM-SMD, was used to predict relative potencies of potential derivatives prior to chemical synthesis. This scheme was successful in distinguishing between high- and low-affinity binders with minimal experimental structural information, saving time and resources in the process. In vitro potency was increased approximately fourfold against GR from the model organism, B. subtilis. Lead derivatives show two- to fourfold increased antimicrobial potency over the parent scaffold. In addition, specificity toward B. subtilis over E. coli and S. aureus depends on the substituent added to the parent scaffold. Finally, insight was gained into the capacity for these compounds to reach the target enzyme in vivo using a bacterial cell wall lysis assay. The outcome of this study is a novel small-molecule inhibitor of GR with the following characteristics: Ki=2.5 μM, LE=0.45 kcal mol(-1) atom(-1), LiPE=6.0, MIC50=260 μg mL(-1) against B. subtilis, EC50, lysis=520 μg mL(-1) against B. subtilis.
Division of Medicinal and Natural Products Chemistry, Department of Biochemistry, University of Iowa, 115 South Grand Avenue, Iowa City, IA 52242 (USA); Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL 61801 (USA).
Katie L
KL
Whalen
Anthony C
AC
Chau
M Ashley
MA
Spies
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008024:Ligands; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D013211:Staphylococcus aureus / Q000187:drug effects; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008024:Ligands; D013451:Sulfonic Acids; C031000:benzimidazole; D000591:Amino Acid Isomerases; C062292:glutamate racemase
antibiotics; fragment‐based drug discovery; glutamate racemase; heterocyclic aromatics; inhibitors