Open AccessCharacterization and Discovery of a Selective Small-Molecule Modulator of Mitochondrial Complex I Targeting a Unique Binding Site
Author(s) -
Jakob C Green,
Yuqi Jiang,
He Li,
Yiming Xu,
Dong Sun,
Timothy Keoprasert,
Christopher A. Nelson,
Unsong Oh,
Edward J. Lesnefsky,
Glen E. Kellogg,
Qun Chen,
Shijun Zhang
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01021
Subject(s) - chemistry , mitochondrion , reactive oxygen species , small molecule , chemical biology , oxidative stress , mechanism of action , bioenergetics , electron transport complex i , drug discovery , biochemistry , biophysics , biology , in vitro , respiratory chain
Mitochondrial dysfunction has been recognized as an essential contributor to many human diseases including neurodegenerative disorders. However, the exact pathological role of mitochondrial dysfunction, especially in mitochondrial reactive oxygen species-associated oxidative stress, remains elusive, partially due to the lack of chemical probes with well-defined mechanisms of action. Herein, we describe the characterization and discovery of a rationally designed small molecule ZCM-I-1 as a selective modulator of the production of reactive oxygen species from mitochondrial complex I that does not alter mitochondrial membrane potential and bioenergetics. Chemical biology studies employing photoaffinity probes derived from ZCM-I-1 demonstrated its novel mechanism of action of modulating complex I via interactions with the flavin mononucleotide site, proximal in the reaction pathway within complex I.