parasite. The CVNVGC redox center at the N-terminal is conserved for all six
species of plasmodium and human isoenzymes. However, the GCGGGKC region at
the C-terminal is found to be preserved in all plasmodium isoforms but not in the
HsTrxR [33]. The parasite has an extended loop at C-terminal which provides
flexibility and good interaction with PfTrx1 substrate [30]. In the RCSB PDB, two
crystal structures of PfTrxR are available in complexation with Trx1 (PDB ID: 4J56,
4J57) and one crystal structure of PfTrxR in the apo-form (PDB ID: 4B1B) [30, 32].
In the PfTrxR, NADPH and FAD cofactors bind to their respective pockets in
each monomer followed by hydride transfer from NADPHto FAD and then subsequently to N-terminal redox center (Cys88 and Cys93). This step is followed by
the subsequent attack of Cys88 (present at the N-terminal of one monomeric
subunit) at Cys540′ (C-terminal of the neighboring monomeric subunit). This in
turn leads to nucleophilic attack of Cys540′ residue on the disulfide bond of
thioredoxin leading to a mixed disulfide bond formation between Cys540′ of
PfTrxR and Cys30 of PfTrx1. Finally, the mixed bond is broken with the help of
Cys535′ (PfTrxR) leading to the release of reduced substrate [30].
Boumis et al. in 2012 suggested the dimer interface cavity to be the site for
non-competitive inhibitors binding in the PfTrxR enzyme. In PfTrxR, a narrow
interface cavity is formed by Tyr101 and His104 residues which in case of HsTrxR are
much wider due to the presence of equivalent Gln72 and Leu75 residues [32]. It was
also observed that smaller and slightly more amphipathic molecules could
have selectivity toward parasite. The PfTrxR enzyme cavity walls have less negative
charge compared to the human isoforms which can be further exploited for selective
inhibitor design [34]. Munigunti et al. in 2013 studied the binding interactions
of five known inhibitors of PfTrxR enzyme (1,4-napthoquinone (1,4-NQ),
bis-(2,4-dinitrophenyl)sulfide (2,4-DNPS), 4-nitrobenzothiadiazole (4-NBT), 3dimethylaminopropiophenone (3-DAP), menadione (MD)) at dimer interface of
PfTrxR and HsTrxR using molecular docking (AutoDock Vina software). It was
observed that Tyr101 residue forms p-p stacking interaction with all the inhibitors
while in HsTrxR due to the presence of Gln72 at the equivalent position shows a
different docking pose in order to avoid steric clashes. The other residues, i.e., Tyr116′
and Ile108, from both monomeric subunits (or only one subunit), form hydrophobic
interaction with the docked inhibitors [34]. Munigunti et al. in 2014 reported similar
residue interactions with curcuminoids at the dimer interface of PfTrxR using Auto
Dock software and suggested that the presence of methoxy group on curcumin
structure reduces the interaction with Tyr101 residue [35]. The aculeatin-like analogues were also reported as inhibitors of PfTrxR enzymes [36].
2.6 P. falciparum Histone Deacetylase (PfHDAC)
Histone deacetylase (HDAC) posttranslationally modifies the histone proteins by
removal of an acetyl group from the e-nitrogen at the lysine side chain (present
within the histone protein) and prevents the accessibility of DNA (wrapped around
186
S. Bhagat et al.
species of plasmodium and human isoenzymes. However, the GCGGGKC region at
the C-terminal is found to be preserved in all plasmodium isoforms but not in the
HsTrxR [33]. The parasite has an extended loop at C-terminal which provides
flexibility and good interaction with PfTrx1 substrate [30]. In the RCSB PDB, two
crystal structures of PfTrxR are available in complexation with Trx1 (PDB ID: 4J56,
4J57) and one crystal structure of PfTrxR in the apo-form (PDB ID: 4B1B) [30, 32].
In the PfTrxR, NADPH and FAD cofactors bind to their respective pockets in
each monomer followed by hydride transfer from NADPHto FAD and then subsequently to N-terminal redox center (Cys88 and Cys93). This step is followed by
the subsequent attack of Cys88 (present at the N-terminal of one monomeric
subunit) at Cys540′ (C-terminal of the neighboring monomeric subunit). This in
turn leads to nucleophilic attack of Cys540′ residue on the disulfide bond of
thioredoxin leading to a mixed disulfide bond formation between Cys540′ of
PfTrxR and Cys30 of PfTrx1. Finally, the mixed bond is broken with the help of
Cys535′ (PfTrxR) leading to the release of reduced substrate [30].
Boumis et al. in 2012 suggested the dimer interface cavity to be the site for
non-competitive inhibitors binding in the PfTrxR enzyme. In PfTrxR, a narrow
interface cavity is formed by Tyr101 and His104 residues which in case of HsTrxR are
much wider due to the presence of equivalent Gln72 and Leu75 residues [32]. It was
also observed that smaller and slightly more amphipathic molecules could
have selectivity toward parasite. The PfTrxR enzyme cavity walls have less negative
charge compared to the human isoforms which can be further exploited for selective
inhibitor design [34]. Munigunti et al. in 2013 studied the binding interactions
of five known inhibitors of PfTrxR enzyme (1,4-napthoquinone (1,4-NQ),
bis-(2,4-dinitrophenyl)sulfide (2,4-DNPS), 4-nitrobenzothiadiazole (4-NBT), 3dimethylaminopropiophenone (3-DAP), menadione (MD)) at dimer interface of
PfTrxR and HsTrxR using molecular docking (AutoDock Vina software). It was
observed that Tyr101 residue forms p-p stacking interaction with all the inhibitors
while in HsTrxR due to the presence of Gln72 at the equivalent position shows a
different docking pose in order to avoid steric clashes. The other residues, i.e., Tyr116′
and Ile108, from both monomeric subunits (or only one subunit), form hydrophobic
interaction with the docked inhibitors [34]. Munigunti et al. in 2014 reported similar
residue interactions with curcuminoids at the dimer interface of PfTrxR using Auto
Dock software and suggested that the presence of methoxy group on curcumin
structure reduces the interaction with Tyr101 residue [35]. The aculeatin-like analogues were also reported as inhibitors of PfTrxR enzymes [36].
2.6 P. falciparum Histone Deacetylase (PfHDAC)
Histone deacetylase (HDAC) posttranslationally modifies the histone proteins by
removal of an acetyl group from the e-nitrogen at the lysine side chain (present
within the histone protein) and prevents the accessibility of DNA (wrapped around
186
S. Bhagat et al.