(4SC-201, Resminostat) [39] were also found to be active against PfHDAC1. These
compounds were found to be less selective for the PfHDAC1 and thus show off
target activity.
2.7 P. falciparum Glutathione S-Transferase (PfGST)
Glutathione S-transferase (GST) is a detoxifying enzyme which catalyzes the
conjugation of glutathione to electrophilic substrates to form conjugated products
that are easily excreted out of body [42]. In plasmodium species, this enzyme
relieves the oxidative stress during the intra-erythrocytic stage of the parasite [43].
Due to its abundance in the parasite cells and increased activity in chloroquineresistant cells, it makes a potential target for antimalarial drug therapy [44].
Wolf et al. in 2003 found that PfGST enzyme exists in dimer–tetramer transition
state. Liebau et al. in 2005 observed that it favors tetrameric inactive state in the
absence of reduce GST and other ligands. Liebau et al. in 2009 demonstrated that
dimer–tetramer transition state is only present in case of PfGST and absent for
HsGST. The active homodimer form is mainly assisted by hydrophobic interactions
in which Phe56 residue of one subunit is buried inside the hydrophobic pocket of
the other subunit formed by Trp131, Phe135, and Tyr134 residues. A hydrogen
bond interaction between side chain of Arg77 and Asp97 residues, present at the
two different neighboring monomeric subunits, also play important role. In typical
l-class human GSTs, the active (G- and H-) sites are present deep in the protein
structure and are shielded by amino acids where as in case of PfGST, these two sites
(G- and H-sites) have more access to solvent. Furthermore, the two non-active
dimers (i.e., inactive forms of the dimer) are interconnected by the loop 113–119
with the help of mainly hydrophobic and a few hydrophilic interactions, leading to
the formation inactive tetramer state. These loop interactions block the active site of
the enzyme and make it inactive [45]. Perbandt et al. later found that whole loop
113–119 is not important for the formation of inactive tetramer state, but Asn112
and Lys117 residues of neighboring subunits are most essential [45]. Other
hydrogen bonds formed by Thr121 and Lys175 also aid to the tetramer formation. It
was identified by Perbandt et al. that the non-substrate binding pocket was occupied
by MES (2-(N-morpholino) ethanesulfonic acid) in its tetrameric form (PDB ID
4ZXG). The non-substrate binding pocket is outlined with Tyr25, Leu26, Leu196,
Pro197, and Asn198 residues. These residues form a highly positively charged
environment which attracts negatively charged ethane sulfonic moiety of MES by
hydrogen bond formation with Asn198 and hydrophobic interaction with other
residues of the cavity [45]. After mutation studies, Tyr9 was identified as an
essential residue for selective inhibition of PfGST [43]. The other inhibitors
reported for the target were S-hexylglutathione [43], Protoporphyrin IX, cibacron
blue, and menadione [46].
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S. Bhagat et al.
compounds were found to be less selective for the PfHDAC1 and thus show off
target activity.
2.7 P. falciparum Glutathione S-Transferase (PfGST)
Glutathione S-transferase (GST) is a detoxifying enzyme which catalyzes the
conjugation of glutathione to electrophilic substrates to form conjugated products
that are easily excreted out of body [42]. In plasmodium species, this enzyme
relieves the oxidative stress during the intra-erythrocytic stage of the parasite [43].
Due to its abundance in the parasite cells and increased activity in chloroquineresistant cells, it makes a potential target for antimalarial drug therapy [44].
Wolf et al. in 2003 found that PfGST enzyme exists in dimer–tetramer transition
state. Liebau et al. in 2005 observed that it favors tetrameric inactive state in the
absence of reduce GST and other ligands. Liebau et al. in 2009 demonstrated that
dimer–tetramer transition state is only present in case of PfGST and absent for
HsGST. The active homodimer form is mainly assisted by hydrophobic interactions
in which Phe56 residue of one subunit is buried inside the hydrophobic pocket of
the other subunit formed by Trp131, Phe135, and Tyr134 residues. A hydrogen
bond interaction between side chain of Arg77 and Asp97 residues, present at the
two different neighboring monomeric subunits, also play important role. In typical
l-class human GSTs, the active (G- and H-) sites are present deep in the protein
structure and are shielded by amino acids where as in case of PfGST, these two sites
(G- and H-sites) have more access to solvent. Furthermore, the two non-active
dimers (i.e., inactive forms of the dimer) are interconnected by the loop 113–119
with the help of mainly hydrophobic and a few hydrophilic interactions, leading to
the formation inactive tetramer state. These loop interactions block the active site of
the enzyme and make it inactive [45]. Perbandt et al. later found that whole loop
113–119 is not important for the formation of inactive tetramer state, but Asn112
and Lys117 residues of neighboring subunits are most essential [45]. Other
hydrogen bonds formed by Thr121 and Lys175 also aid to the tetramer formation. It
was identified by Perbandt et al. that the non-substrate binding pocket was occupied
by MES (2-(N-morpholino) ethanesulfonic acid) in its tetrameric form (PDB ID
4ZXG). The non-substrate binding pocket is outlined with Tyr25, Leu26, Leu196,
Pro197, and Asn198 residues. These residues form a highly positively charged
environment which attracts negatively charged ethane sulfonic moiety of MES by
hydrogen bond formation with Asn198 and hydrophobic interaction with other
residues of the cavity [45]. After mutation studies, Tyr9 was identified as an
essential residue for selective inhibition of PfGST [43]. The other inhibitors
reported for the target were S-hexylglutathione [43], Protoporphyrin IX, cibacron
blue, and menadione [46].
188
S. Bhagat et al.