Design of Inhibitors of the MurF Enzyme of Streptococcus pneumoniae Using Docking, 3D-QSAR, and de Novo Design

Khedkar, Santosh A., Malde, Alpeshkumar K. and Coutinho, Evans C. (2007) Design of Inhibitors of the MurF Enzyme of Streptococcus pneumoniae Using Docking, 3D-QSAR, and de Novo Design. Journal of Chemical Information & Modeling, 47 5: 1839-1846. doi:10.1021/ci600568u


Author Khedkar, Santosh A.
Malde, Alpeshkumar K.
Coutinho, Evans C.
Title Design of Inhibitors of the MurF Enzyme of Streptococcus pneumoniae Using Docking, 3D-QSAR, and de Novo Design
Journal name Journal of Chemical Information & Modeling   Check publisher's open access policy
ISSN 1549-9596
Publication date 2007-09
Sub-type Article (original research)
DOI 10.1021/ci600568u
Volume 47
Issue 5
Start page 1839
End page 1846
Total pages 7
Place of publication Washington, D.C., U.S.A
Publisher American Chemical Society
Language eng
Subject 030402 Biomolecular Modelling and Design
030404 Cheminformatics and Quantitative Structure-Activity Relationships
Abstract The biosynthetic pathway for formation of the bacterial cell wall (peptidoglycan) presents an attractive target for intervention. This is exploited by many of the clinically useful antibiotics, which inhibit enzymes involved in the later stages of peptidoglycan synthesis. MurF is one of the four amide bond-forming enzymes (d-alanyl−d-alanine ligating enzyme) that catalyzes the ATP-dependent formation of UDP-MurNAc-tripeptide. In the present study, several MurF inhibitors were docked into the active site of MurF to explore their binding modes and also to gain an insight into the crucial ligand−receptor interactions at the molecular level. The final selection of the “bioactive” conformation of every ligand was influenced by consensus scoring in which various independent scoring functions such as GoldScore, ChemScore, HINT score and X-CScore were employed. Subsequently, 3D-QSAR studies using comparative molecular field analysis (CoMFA) and the new approach comparative residue interaction analysis (CoRIA) have been carried out on the enzyme−inhibitor complexes obtained by docking and postscoring analysis. Finally, new inhibitors have been designed using the de novo approach of Ludi, and the activities of the most promising hits have been predicted with the CoMFA and CoRIA models.
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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