Katie Whalen - In silico Optimization of a Fragment-Based Hit Yields Biologically Active, High-Efficiency Inhibitors for Glutamate Racemase.

Version 1

      Publication Details (including relevant citation   information):

      Whalen KL, Chau AC, Spies MA.

      ChemMedChem. 2013   Aug 8. doi: 10.1002/cmdc.201300271. [Epub ahead of print]

     

     
       
          PMID: 23929705      [PubMed -       as supplied by publisher]   
     

      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.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/23929705