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

Journal Article · · ChemBioChem: a European journal of chemical biology
 [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
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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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
DOE Contract Number:
AC02-05CH11231
OSTI ID:
1435085
Journal Information:
ChemBioChem: a European journal of chemical biology, Journal Name: ChemBioChem: a European journal of chemical biology Journal Issue: 10 Vol. 18; ISSN 1439-4227
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
English

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