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Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non‐diphosphate Inhibitors
Author(s) -
O'Dowd Bing,
Williams Sarah,
Wang Hongxin,
No Joo Hwan,
Rao Guodong,
Wang Weixue,
McCammon J. Andrew,
Cramer Stephen P.,
Oldfield Eric
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700052
Subject(s) - ligand (biochemistry) , chemistry , stereochemistry , in silico , molecule , drug discovery , substrate (aquarium) , small molecule , biochemistry , biology , receptor , ecology , gene , organic chemistry
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 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 n m against Pseudomonas aeruginosa IspH.