were identified to in vitro activity against PfDHFR and one compound was found to
be curative against Plasmodium berghei during in vivo studies [12].
In 2017 itself, 21 crystal structures of recently discovered targets of Plasmodium
falciparum were reported in RCSB Protein Data Bank. Given the extensive
development in availability of high-resolution crystal structures of various important targets and techniques available to analyze these targets, the opportunities to
carry out SBDD are enormous. Also, the availability of crystal structures of mutated
enzymes offers opportunities to understand the reasons for mutation, its effect on
the parasite and modifications required to overcome these mutations. The purpose
of this review is to understand the SBDD efforts involved in the identification of
new leads for malaria taking example of PfDHODH as a target.
2 New Targets for Antimalarial Agent Design
Employing SBDD
2.1 P. falciparum ATP-Dependent Heat Shock Protein 90
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone involved
in the protein folding, stabilization, and protein–protein interaction of a variety of
different proteins such as E3 ligases, transcription factors, various kinases, and
many other proteins [6a]. It thus plays a major role in signal transduction and
cell-cycle regulation of various species including P. falciparum [13]. Various
inhibitors including geldanamycin (anticancer drug) compete with the natural
substrate (ATP) for occupying the ATP-binding domain present at the N-terminal
of the protein. This inhibition results in the arrest of the parasite growth in
intra-erythrocytic phase by blocking the transition from immature ring-form stage
to maturetrophozoite stage [13].
It is a homodimer protein and has three functional domains: (1) ATP-binding
domain present at N-terminal, (2) a middle domain which facilitates ATP turnover,
and (3) C-terminal domain which helps in dimerization. The ATPase cycle begins
with the binding of substrate protein (like transcription factors, transducers) on the
hydrophobic interface between the N-terminal and middle domains. This is followed by ATP binding and its subsequent hydrolysis that resulting in the compression of the substrate protein [14]. Its inhibitors bind to the ATP-binding site and
halt conformational changes which are necessary to convert protein into compact
one. The crystal structure reveals that PfHsp90 enzyme (PDB ID: 3K60) comprises
of seven a-helices on one side and nine antiparallel b-sheets on other side of
enzyme. The ATP binds to the solvent-accessible surface between a b-sheet and
several a-helices. Hsp90 in all the species is characterized by the presence of an
ATP lid (with different length, tertiary structure, and conformation) which is formed
by the loop connecting the b-sheets and a-helices [13b].
180
S. Bhagat et al.
be curative against Plasmodium berghei during in vivo studies [12].
In 2017 itself, 21 crystal structures of recently discovered targets of Plasmodium
falciparum were reported in RCSB Protein Data Bank. Given the extensive
development in availability of high-resolution crystal structures of various important targets and techniques available to analyze these targets, the opportunities to
carry out SBDD are enormous. Also, the availability of crystal structures of mutated
enzymes offers opportunities to understand the reasons for mutation, its effect on
the parasite and modifications required to overcome these mutations. The purpose
of this review is to understand the SBDD efforts involved in the identification of
new leads for malaria taking example of PfDHODH as a target.
2 New Targets for Antimalarial Agent Design
Employing SBDD
2.1 P. falciparum ATP-Dependent Heat Shock Protein 90
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone involved
in the protein folding, stabilization, and protein–protein interaction of a variety of
different proteins such as E3 ligases, transcription factors, various kinases, and
many other proteins [6a]. It thus plays a major role in signal transduction and
cell-cycle regulation of various species including P. falciparum [13]. Various
inhibitors including geldanamycin (anticancer drug) compete with the natural
substrate (ATP) for occupying the ATP-binding domain present at the N-terminal
of the protein. This inhibition results in the arrest of the parasite growth in
intra-erythrocytic phase by blocking the transition from immature ring-form stage
to maturetrophozoite stage [13].
It is a homodimer protein and has three functional domains: (1) ATP-binding
domain present at N-terminal, (2) a middle domain which facilitates ATP turnover,
and (3) C-terminal domain which helps in dimerization. The ATPase cycle begins
with the binding of substrate protein (like transcription factors, transducers) on the
hydrophobic interface between the N-terminal and middle domains. This is followed by ATP binding and its subsequent hydrolysis that resulting in the compression of the substrate protein [14]. Its inhibitors bind to the ATP-binding site and
halt conformational changes which are necessary to convert protein into compact
one. The crystal structure reveals that PfHsp90 enzyme (PDB ID: 3K60) comprises
of seven a-helices on one side and nine antiparallel b-sheets on other side of
enzyme. The ATP binds to the solvent-accessible surface between a b-sheet and
several a-helices. Hsp90 in all the species is characterized by the presence of an
ATP lid (with different length, tertiary structure, and conformation) which is formed
by the loop connecting the b-sheets and a-helices [13b].
180
S. Bhagat et al.