1. In silico optimization of a fragment-based hit yields biologically active, high-efficiency inhibitors for glutamate racemase.
- Author
-
Whalen KL, Chau AC, and Spies MA
- Subjects
- Amino Acid Isomerases metabolism, Anti-Bacterial Agents pharmacology, Bacillus subtilis drug effects, Benzimidazoles chemistry, Binding Sites, Catalytic Domain, Drug Design, Enzyme Inhibitors pharmacology, Escherichia coli drug effects, Ligands, Microbial Sensitivity Tests, Molecular Docking Simulation, Staphylococcus aureus drug effects, Sulfonic Acids chemical synthesis, Sulfonic Acids chemistry, Sulfonic Acids pharmacology, Amino Acid Isomerases antagonists & inhibitors, Anti-Bacterial Agents chemistry, Enzyme Inhibitors chemistry
- Abstract
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., (Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF