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

Abstract

Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target described 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 η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) 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 K i value of ≈500 nm against Pseudomonas aeruginosa IspH.

Authors:
 [1];  [2];  [3];  [4];  [1];  [4];  [5];  [3];  [1]
  1. Department of Chemistry, University of Illinois, 600 South Mathews Avenue Urbana IL 61801 USA
  2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA
  3. Department of Chemistry, University of California, 1 Shields Avenue Davis CA 95616 USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Road Berkeley CA 94720 USA
  4. Center for Biophysics and Computational Biology, Urbana, IL (United States)
  5. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla CA 92093 USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla CA 92093 USA; National Biomedical Computation Resource, University of California at San Diego, La Jolla CA 92093 USA
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1435085
DOE Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
ChemBioChem: a European journal of chemical biology
Additional Journal Information:
Journal Volume: 18; Journal Issue: 10; Journal ID: ISSN 1439-4227
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., and Oldfield, Eric. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors. United States: N. p., 2017. Web. doi:10.1002/cbic.201700052.
O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., & Oldfield, Eric. Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors. United States. doi:10.1002/cbic.201700052.
O'Dowd, Bing, Williams, Sarah, Wang, Hongxin, No, Joo Hwan, Rao, Guodong, Wang, Weixue, McCammon, J. Andrew, Cramer, Stephen P., and Oldfield, Eric. Fri . "Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors". United States. doi:10.1002/cbic.201700052.
@article{osti_1435085,
title = {Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors},
author = {O'Dowd, Bing and Williams, Sarah and Wang, Hongxin and No, Joo Hwan and Rao, Guodong and Wang, Weixue and McCammon, J. Andrew and Cramer, Stephen P. and Oldfield, Eric},
abstractNote = {Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target described 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 η 1 coordination, forming tetrahedral geometries at the unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) 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 K i value of ≈500 nm against Pseudomonas aeruginosa IspH.},
doi = {10.1002/cbic.201700052},
journal = {ChemBioChem: a European journal of chemical biology},
issn = {1439-4227},
number = 10,
volume = 18,
place = {United States},
year = {2017},
month = {4}
}

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