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In silico Optimization of a Fragment‐Based Hit Yields Biologically Active, High‐Efficiency Inhibitors for Glutamate Racemase
Author(s) -
Whalen Katie L.,
Chau Anthony C.,
Spies M. Ashley
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300271
Subject(s) - ligand efficiency , bacillus subtilis , lysis , chemistry , docking (animal) , lead compound , substituent , in silico , potency , in vivo , stereochemistry , pharmacophore , small molecule , enzyme , combinatorial chemistry , structure–activity relationship , ligand (biochemistry) , in vitro , biochemistry , antibacterial activity , biology , bacteria , receptor , medicine , nursing , microbiology and biotechnology , gene , genetics
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: K i =2.5 μ M , LE=0.45 kcal mol −1 atom −1 , LiPE=6.0, MIC 50 =260 μg mL −1 against B. subtilis , EC 50, lysis =520 μg mL −1 against B. subtilis .