ArticleChemMedChem2013
In silico optimization of a fragment-based hit yields biologically active, high-efficiency inhibitors for glutamate racemase.
Article in ChemMedChem, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 13 citations in OpenAlex.
- Heterologous expression, purification and biochemical characterization of a glutamate racemase (MurI) fromPeerJ · 2019Article
- Elucidating the Catalytic Power of Glutamate Racemase by Investigating a Series of Covalent Inhibitors.ChemMedChem · 2018Article
- Synthesis, anti-bacterial and anti-protozoal activities of amidinobenzimidazole derivatives and their interactions with DNA and RNA.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Integrating Experimental and In Silico HTS in the Discovery of Inhibitors of Protein-Nucleic Acid Interactions.Methods in enzymology · 2018Article
- Ensemble-based docking: From hit discovery to metabolism and toxicity predictions.Bioorganic & medicinal chemistry · 2016Article
- Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.PloS one · 2016Article
- Nexus between protein-ligand affinity rank-ordering, biophysical approaches, and drug discovery.ACS medicinal chemistry letters · 2013Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.