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Investigating the Selectivity of Metalloenzyme Inhibitors in the Presence of Competing Metalloproteins
Author(s) -
Chen Yao,
Cohen Seth M.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500293
Subject(s) - metalloprotein , chemistry , small molecule , carbonic anhydrase , computational biology , protein–protein interaction , biochemistry , combinatorial chemistry , enzyme , biology
Metalloprotein inhibitors (MPi) are an important class of therapeutics for the treatment of a variety of diseases, including hypertension, cancer, and HIV/AIDS. However, despite their clinical success, there is an apprehension that MPi may be less selective than other small‐molecule therapeutics and more prone to inhibit off‐target metalloenzymes. We examined the issue of MPi specificity by investigating the selectivity of a variety of MPi against a representative panel of metalloenzymes in the presence of competing metalloproteins (metallothionein, myoglobin, carbonic anhydrase, and transferrin). Our findings reveal that a wide variety of MPi do not exhibit a decrease in inhibitory activity in the presence of large excesses of competing metalloproteins, suggesting that the competing proteins do not titrate the MPi away from its intended target. This study represents a rudimentary but important means to mimic the biological milieu, which contains other metalloproteins that could compete the MPi away from its target. The strategy used in this study may be a useful approach to examine the selectivity of other MPi in development.