mainly based on the hydrogen binding ability, atom polarizability, and ring
complexity.
Pavadai et al. performed a systematic search of identification of species-selective
PfDHODH inhibitors by performing 3D-QSAR pharmacophore modeling followed
by molecular docking-based virtual screening [96]. The final filtered compounds
were tested for their PfDHODH inhibitory activity and antimalarial activity. For
3D-QSAR model generation, a total of 38 compounds were selected from the work
of Xu et al. on dihydrothiophenone class of compounds [84]. These are divided into
training set (19 compounds) (activity range 6–39,450 nM) and test set (19 compounds). A total of 250 conformers were generated for these compounds. Hypogen
algorithm was used to generate the pharmacophore hypotheses. Based on high
correlation coefficient (r), low cost and low root mean square (RMS), a total of top
ten hypotheses were selected. Based on the model, validation results based on test
set prediction and cost values Hypo1 (test set correlation, r = 0.933) were selected
for further virtual screening. 265,242 compounds from NCI database were used as
query. The hit compounds were selected based on the features of the pharmacophore model and the hit compounds undergo molecular docking studies using
PfDHODH crystal structure (PDB ID 3I65) using Glide module of Schrödinger
software. The molecules selected from standard precision docking based on the
score and poses were filtered through extra precision docking. The top-ranked
molecules obtained after this analysis were subjected to prime MM-GBSA calculations to calculate DG Bind . The sixty-two compounds obtained after the thorough
virtual screening process were subjected to biological testing in which three compounds were identified to exhibit PfDHODH activity in the range of 0.38–20 µM
IC 50 value. The most active compound (NSC336047) showed selectivity against
HsDHODH (IC 50 > 100 µM) and inhibition of parasite growth with 26 µM IC 50
value [96].
4 Conclusions
SBDD proved to be a successful approach in the design of antimalarial agents. With
the expanding knowledge into the new targets and enzymes essential for malarial
parasite survival, it has become less straining in discovering or modifying the lead
molecules based on the structural knowledge of the target. Some of these targets are
PfATP-dependent heat shock protein 90, Pfphosphatidylinositol 4-kinase (PI4 K),
PfNADH dehydrogenase, Pfaspartate carbamoyltransferase, Pfthioredoxin reductase, Pfhistone deacetylase, and Pf dihydroorotate dehydrogenase.
Taking an example of PfDHODH, all the SBDD efforts related to this target
were discussed. This enzyme was found to be important for the synthesis of
pyrimidines in the parasite through de novo pathway. As this enzyme is also a part
of the mitochondrial respiratory chain complex, its inhibition also affects the
electron transfer in the inner mitochondrial membrane. The overall reaction
involves the redox hip-hop mechanism in which DHO is oxidized by FMN to ORO.
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S. Bhagat et al.
complexity.
Pavadai et al. performed a systematic search of identification of species-selective
PfDHODH inhibitors by performing 3D-QSAR pharmacophore modeling followed
by molecular docking-based virtual screening [96]. The final filtered compounds
were tested for their PfDHODH inhibitory activity and antimalarial activity. For
3D-QSAR model generation, a total of 38 compounds were selected from the work
of Xu et al. on dihydrothiophenone class of compounds [84]. These are divided into
training set (19 compounds) (activity range 6–39,450 nM) and test set (19 compounds). A total of 250 conformers were generated for these compounds. Hypogen
algorithm was used to generate the pharmacophore hypotheses. Based on high
correlation coefficient (r), low cost and low root mean square (RMS), a total of top
ten hypotheses were selected. Based on the model, validation results based on test
set prediction and cost values Hypo1 (test set correlation, r = 0.933) were selected
for further virtual screening. 265,242 compounds from NCI database were used as
query. The hit compounds were selected based on the features of the pharmacophore model and the hit compounds undergo molecular docking studies using
PfDHODH crystal structure (PDB ID 3I65) using Glide module of Schrödinger
software. The molecules selected from standard precision docking based on the
score and poses were filtered through extra precision docking. The top-ranked
molecules obtained after this analysis were subjected to prime MM-GBSA calculations to calculate DG Bind . The sixty-two compounds obtained after the thorough
virtual screening process were subjected to biological testing in which three compounds were identified to exhibit PfDHODH activity in the range of 0.38–20 µM
IC 50 value. The most active compound (NSC336047) showed selectivity against
HsDHODH (IC 50 > 100 µM) and inhibition of parasite growth with 26 µM IC 50
value [96].
4 Conclusions
SBDD proved to be a successful approach in the design of antimalarial agents. With
the expanding knowledge into the new targets and enzymes essential for malarial
parasite survival, it has become less straining in discovering or modifying the lead
molecules based on the structural knowledge of the target. Some of these targets are
PfATP-dependent heat shock protein 90, Pfphosphatidylinositol 4-kinase (PI4 K),
PfNADH dehydrogenase, Pfaspartate carbamoyltransferase, Pfthioredoxin reductase, Pfhistone deacetylase, and Pf dihydroorotate dehydrogenase.
Taking an example of PfDHODH, all the SBDD efforts related to this target
were discussed. This enzyme was found to be important for the synthesis of
pyrimidines in the parasite through de novo pathway. As this enzyme is also a part
of the mitochondrial respiratory chain complex, its inhibition also affects the
electron transfer in the inner mitochondrial membrane. The overall reaction
involves the redox hip-hop mechanism in which DHO is oxidized by FMN to ORO.
214
S. Bhagat et al.