Medicinal Chemistry Research

, Volume 21, Issue 3, pp 362–372

A ligand-based approach for enhancing the pharmacokinetic profile of highly charged antibacterial agents

Authors

  • Kyle W. Skidmore
    • Department of Pharmaceutical and Biomedical Sciences, Raabe College of PharmacyOhio Northern University
    • Fayette Regional Health System Pharmacy
  • Corey Scherer
    • Department of BiologyOhio Northern University
    • Lake Erie College of Osteopathic Medicine
  • Amy Stockert
    • Department of Pharmaceutical and Biomedical Sciences, Raabe College of PharmacyOhio Northern University
    • Department of Pharmaceutical and Biomedical Sciences, Raabe College of PharmacyOhio Northern University
Original Research

DOI: 10.1007/s00044-010-9538-4

Cite this article as:
Skidmore, K.W., Scherer, C., Stockert, A. et al. Med Chem Res (2012) 21: 362. doi:10.1007/s00044-010-9538-4

Abstract

Glutamate racemase catalyses the interconversion of l-glutamate and d-glutamate making available d-glutamate which is essential for peptidoglycan biosynthesis. Inhibitors of this enzyme have exhibited antibacterial activity with the d-glutamate-analogues group of inhibitors being the most significant as it is the only group that has demonstrated efficacy in a murine thigh Streptococcus pneumoniae infection model. This group of inhibitors, however, showed a narrow antibacterial spectrum that could be due to poor lipophilicity and permeability properties. Here, we have adopted a computational ligand-based drug design approach to enhance the lipophilicity and, hence, the antibacterial spectrum of this group of inhibitors. By limiting the charged groups on our pharmacophore model and identifying key interactions for glutamate racemase binding and inhibition, we have successfully searched a compound database for compounds with both antibacterial activity and increased lipophilicity. However, our compounds appear less potent, likely due to decreased specificity. We also demonstrate that permeability and lipophilicity alone are not responsible for the narrow antibacterial spectrum observed in the d-glutamate analogue inhibitors.

Keywords

PharmacophoreADMELipophilicityPharmacokinetic properties

Copyright information

© Springer Science+Business Media, LLC 2011