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In silico Optimization of a Fragment-Based Hit Yields Biologically Active, High-Efficiency Inhibitors for Glutamate Racemase
Journal article   Open access   Peer reviewed

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

Katie L Whalen, Anthony C Chau and M. Ashley Spies
ChemMedChem, Vol.8(10), pp.1681-n/a
08/08/2013
DOI: 10.1002/cmdc.201300271
PMCID: PMC4040332
PMID: 23929705
url
https://doi.org/10.1002/cmdc.201300271View
Published (Version of record) Open Access

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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