BRENDA - Enzyme Database

First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness

Smith, T.K.; Young, B.L.; Denton, H.; Hughes, D.L.; Wagner, G.K.; Bioorg. Med. Chem. Lett. 19, 1749-1752 (2009)

Data extracted from this reference:

Application
EC Number
Application
Commentary
Organism
2.4.1.83
drug development
inhibition of DPMS is a promising strategy for the development of anti-trypanosomal agents. Thiazolidinones [(5Z)-5-[[4-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid, [(5Z)-5-[[3,4-bis(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid and [(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid in particular are promising candidates for further development because of their respective activities against trypanosomal DPMS and GPI anchor biosynthesis
Trypanosoma brucei
Cloned(Commentary)
EC Number
Commentary
Organism
2.4.1.83
full-length DPMS expressed in Escherichia coli
Trypanosoma brucei
Inhibitors
EC Number
Inhibitors
Commentary
Organism
Structure
2.4.1.83
additional information
DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol anchors, and possess trypanocidal activity against live trypanosomes
Trypanosoma brucei
2.4.1.83
[(5Z)-4-oxo-5-(phenylmethylidene)-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
42% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
23% residual DPMS activity in the presence of 1 mM. Does not affect dolichyl D-mannosyl phosphate production in the cell-free system, but potently inhibits formation of mannosylated glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(3-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
90% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-chlorophenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
86% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-cyanophenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
73% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-ethynylphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
94% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
70% residual DPMS activity in the presence of 1 mM. Abolishes the formation of dolichyl D-mannosyl phosphate almost completely, and significantly reduces the formation of downstream glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[3,4-bis(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
20% residual DPMS activity in the presence of 1 mM. Abolishes the formation of dolichyl D-mannosyl phosphate almost completely, and significantly reduces the formation of downstream glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[3-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
23% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[4-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
10% residual DPMS activity in the presence of 1 mM. Does not affect dolichyl D-mannosyl phosphate production in the cell-free system, but potently inhibits formation of mannosylated glycosylphosphatidylinositol intermediates
Trypanosoma brucei
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
2.4.1.83
Trypanosoma brucei
-
-
-
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
2.4.1.83
GDP-mannose + dolichyl phosphate
-
702559
Trypanosoma brucei
GDP + dolichyl D-mannosyl phosphate
-
-
-
?
2.4.1.83
additional information
glycosylphosphatidylinositol anchor biosynthesis
702559
Trypanosoma brucei
?
-
-
-
-
Application (protein specific)
EC Number
Application
Commentary
Organism
2.4.1.83
drug development
inhibition of DPMS is a promising strategy for the development of anti-trypanosomal agents. Thiazolidinones [(5Z)-5-[[4-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid, [(5Z)-5-[[3,4-bis(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid and [(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid in particular are promising candidates for further development because of their respective activities against trypanosomal DPMS and GPI anchor biosynthesis
Trypanosoma brucei
Cloned(Commentary) (protein specific)
EC Number
Commentary
Organism
2.4.1.83
full-length DPMS expressed in Escherichia coli
Trypanosoma brucei
Inhibitors (protein specific)
EC Number
Inhibitors
Commentary
Organism
Structure
2.4.1.83
additional information
DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol anchors, and possess trypanocidal activity against live trypanosomes
Trypanosoma brucei
2.4.1.83
[(5Z)-4-oxo-5-(phenylmethylidene)-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
42% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(2-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
23% residual DPMS activity in the presence of 1 mM. Does not affect dolichyl D-mannosyl phosphate production in the cell-free system, but potently inhibits formation of mannosylated glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(3-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
90% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-chlorophenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
86% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-cyanophenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
73% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-ethynylphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
94% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[(4-hydroxyphenyl)methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
70% residual DPMS activity in the presence of 1 mM. Abolishes the formation of dolichyl D-mannosyl phosphate almost completely, and significantly reduces the formation of downstream glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[3,4-bis(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
20% residual DPMS activity in the presence of 1 mM. Abolishes the formation of dolichyl D-mannosyl phosphate almost completely, and significantly reduces the formation of downstream glycosylphosphatidylinositol intermediates
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[3-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
23% residual DPMS activity in the presence of 1 mM
Trypanosoma brucei
2.4.1.83
[(5Z)-5-[[4-(benzyloxy)phenyl]methylidene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]acetic acid
10% residual DPMS activity in the presence of 1 mM. Does not affect dolichyl D-mannosyl phosphate production in the cell-free system, but potently inhibits formation of mannosylated glycosylphosphatidylinositol intermediates
Trypanosoma brucei
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
2.4.1.83
GDP-mannose + dolichyl phosphate
-
702559
Trypanosoma brucei
GDP + dolichyl D-mannosyl phosphate
-
-
-
?
2.4.1.83
additional information
glycosylphosphatidylinositol anchor biosynthesis
702559
Trypanosoma brucei
?
-
-
-
-