Abstract:The human lactate dehydrogenase isoform A plays an important role in the
anaerobic metabolism of tumour cells and therefore constitutes an attractive
target in the oncology field. Full-atom models of lactate dehydrogenase A (in
complex with NADH and in the apo form) have been generated to enable
structure-based design of novel inhibitors competing with pyruvate and NADH.
The structural criteria for the selection of potential inhibitors were
established, and virtual screening of a library of low-molecular-weigh… Show more
“…1C). The concentration at which PSTMB inhibits LDHA activity (IC 50 = 145.2 nM) was much lower than that of oxamate (IC 50 = 130.6 μM), a standard inhibitor of LDHA 18–20 .Figure 1PSTMB has a potent inhibitory effect on in vitro LDHA activity. ( A ) Structures of the selenobenzene compounds analyzed in this study are shown.…”
The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.
“…1C). The concentration at which PSTMB inhibits LDHA activity (IC 50 = 145.2 nM) was much lower than that of oxamate (IC 50 = 130.6 μM), a standard inhibitor of LDHA 18–20 .Figure 1PSTMB has a potent inhibitory effect on in vitro LDHA activity. ( A ) Structures of the selenobenzene compounds analyzed in this study are shown.…”
The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.
“…The IC 50 value was determined to be 1.2 mM. Interestingly, inhibitor 4 binds in a similar manner to the earlier
investigated oxamate derivative STK381370 (ΔGcalc = –7.9 kcal/mol,
IC 50 5 mM) [24],
forming additional interactions with the loop 96–111. However, the interaction
of 4 is more efficient.…”
Section: Resultsmentioning
confidence: 60%
“…This rule defines the ranges of
physicochemical parameters associated with molecule fragments (molecular weight
< 300, log P ≤ 3, hydrogen bond donors ≤ 3,
hydrogen bond acceptors ≤ 3, and rotatable bonds ≤ 3). Molecular
docking of compounds from the obtained focused library was performed using Lead
Finder 1.1.15 in the “extra precision” mode [29, 30] and the models
of human LDH-A (with and without the bound molecule of NADH) constructed in our
previous work [24]. At the first step of
the selection of inhibitors, some compounds were eliminated when the distance
between the sulfur of the sulfo group and the guanidinium carbon of Arg168 at
their binding with LDH-A exceeded 5.5 A.…”
Section: Methodsmentioning
confidence: 99%
“…At the first step of
the selection of inhibitors, some compounds were eliminated when the distance
between the sulfur of the sulfo group and the guanidinium carbon of Arg168 at
their binding with LDH-A exceeded 5.5 A. The remaining compounds that fitted
the criteria of the structural filtration were tested for their ability to form
hydrogen bonds and hydrophobic contacts with residues of the loop 96–111
[24]. Visualization and analysis of the
structures were performed using VMD 1.9.2 [31].…”
Human lactate dehydrogenase A plays an important role in the glucose metabolism
of tumor cells and constitutes an attractive target for chemotherapy. Molecular
fragments able to bind in the active site of this enzyme and form hydrogen
bonds with the Arg168 guanidinium group, as well as additional interactions
with the loop 96–111 in the closed conformation, have been identified by
virtual screening of sulfonates and experimental testing of their inhibitory
effect. The sulfo group can occupy a similar position as the carboxyl group of
the substrate and its structural analogs, whereas the benzothiazole group
attached via a linker can be located in the coenzyme (NADH) binding site. Thus,
the value of merging individual structural elements of the inhibitor by a
linker was demonstrated and ways of further structural modification for the
design of more effective inhibitors of lactate dehydrogenase A were established.
“…To alter the
catalytic properties of an enzyme random mutations are introduced into the
structure of the active site [71]. Similarly, the majority of the developed drugs bind to functional centers of
proteins (see [72] as an example). Practical application of allosteric sites is arguably rare, although some
examples are known.…”
Section: Binding Sites In Biotechnology and Biomedicinementioning
The interaction of proteins (enzymes) with a variety of low-molecular-weight
compounds, as well as protein-protein interactions, is the most important
factor in the regulation of their functional properties. To date, research
effort has routinely focused on studying ligand binding to the functional sites
of proteins (active sites of enzymes), whereas the molecular mechanisms of
allosteric regulation, as well as binding to other pockets and cavities in
protein structures, remained poorly understood. Recent studies have shown that
allostery may be an intrinsic property of virtually all proteins. Novel
approaches are needed to systematically analyze the architecture and role of
various binding sites and establish the relationship between structure,
function, and regulation. Computational biology, bioinformatics, and molecular
modeling can be used to search for new regulatory centers, characterize their
structural peculiarities, as well as compare different pockets in homologous
proteins, study the molecular mechanisms of allostery, and understand the
communication between topologically independent binding sites in protein
structures. The establishment of an evolutionary relationship between different
binding centers within protein superfamilies and the discovery of new
functional and allosteric (regulatory) sites using computational approaches can
improve our understanding of the structure-function relationship in proteins
and provide new opportunities for drug design and enzyme engineering.
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