Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors

Bing O'Dowd, Sarah Williams, Hongxin Wang, Joo Hwan No, Guodong Rao, Weixue Wang, J. Andrew McCammon, Stephen P. Cramer, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H+/2e reduction. IspH contains a 4 Fe−4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe−4 S clusters by η1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H2O, O2) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a Ki value of ≈500 nm against Pseudomonas aeruginosa IspH.

Original languageEnglish (US)
Pages (from-to)914-920
Number of pages7
JournalChemBioChem
Volume18
Issue number10
DOIs
StatePublished - May 18 2017

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Keywords

  • HYSCORE
  • IspH
  • NRVS
  • in silico
  • isoprenoid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

O'Dowd, B., Williams, S., Wang, H., No, J. H., Rao, G., Wang, W., McCammon, J. A., Cramer, S. P., & Oldfield, E. (2017). Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors. ChemBioChem, 18(10), 914-920. https://doi.org/10.1002/cbic.201700052