The inhibitor binding site was predicted to be near to ubiquinone-binding site due to
non-conserved nature of amino acids in this region and reoxidation of FMN was
characterized to be the rate-limiting step.
The enzyme consists of a b-barrel core of eight parallel b-sheets surrounded by
seven a-helices. The top and bottom of the barrel is covered by antiparallel
b-strands, three on one side and two on side attached to N-terminal. The inhibitor
binding site is located between the a10–a11 helices of the N-terminal. There are
fifteen crystal structures reported for PfDHODH till date. The first reported X-ray
crystal structure with PDB ID 1TV5 containing teriflunomide as the co-crystallized
inhibitor discusses about the important hydrogen bonding interactions shown by
His185 and Arg265 at the end of the inhibitor binding tunnel. Later, two new
hydrophobic binding pockets were reported in crystal structure 3I6R (DSM74 as
co-crystallized ligand) and 3O8A (Genz-669178 as co-crystallized ligand).
A total of nine important chemical classes of PfDHODH inhibitors are reported
in the literature. Out of these triazolopyrimidine derivatives and N-alkyl-5benzimidazole thiophene-2-carboxamide analogs were found to be most suitable
with IC 50 values in lower nanomolar range. The SBDD approach is facilitated in the
designing of lead molecules with optimal in vitro and in vivo activity, good
metabolic profile with minimum toxicity along with selectivity against HsDHODH.
DSM265 has been is under clinical development and Genz-669178 is understudy
for clinical trials suitability. Various in silico studies are also reported which mainly
include 3D-QSAR studies/molecular docking/molecular dynamics.
Acknowledgements The University Grants Commission is gratefully acknowledged for the
financial support to Shweta Bhagat (UGC, Grant No. 43395). The authors thank Department of
Science and Technology (DST), Government of India, New Delhi, India, for financial support.
References
1. World Malaria Report (2017) World Health Organization, Geneva. doi: ISBN
978-92-4-156552-3
2. [a] Gregson A, Plowe CV (2005) Mechanisms of resistance of malaria parasites to antifolates.
Pharmacol Rev 57:117–145; [b] Harinasuta T, Suntharasamai P, Viravan C (1965)
Chloroquine-resistant falciparum malaria in Thailand. The Lancet 2:657–660; [c]
Sirawaraporn W, Prapunwattana P et al. (1993) The dihydrofolate reductase domain of
Plasmodium falciparum thymidylate synthase-dihydrofolate reductase. Gene synthesis,
expression, and anti-folate-resistant mutants. J Biol Chem 268:21637–21644
3. Wells TNC, van Huijsduijnen RH, Van Voorhis WC (2015) Malaria medicines: a glass half
full? Nat Rev Drug Discov 14:424–442
4. Tinto H, D’Alessandro U et al (2015) Efficacy and safety of RTS, S/AS01 malaria vaccine
with or without a booster dose in infants and children in Africa: final results of a phase 3,
individually randomised, controlled trial. The Lancet 386:31–45
5. Anderson AC (2003) The process of structure-based drug design. Chem Biol 10:787–797
Structure-Based Design of PfDHODH Inhibitors …
215
non-conserved nature of amino acids in this region and reoxidation of FMN was
characterized to be the rate-limiting step.
The enzyme consists of a b-barrel core of eight parallel b-sheets surrounded by
seven a-helices. The top and bottom of the barrel is covered by antiparallel
b-strands, three on one side and two on side attached to N-terminal. The inhibitor
binding site is located between the a10–a11 helices of the N-terminal. There are
fifteen crystal structures reported for PfDHODH till date. The first reported X-ray
crystal structure with PDB ID 1TV5 containing teriflunomide as the co-crystallized
inhibitor discusses about the important hydrogen bonding interactions shown by
His185 and Arg265 at the end of the inhibitor binding tunnel. Later, two new
hydrophobic binding pockets were reported in crystal structure 3I6R (DSM74 as
co-crystallized ligand) and 3O8A (Genz-669178 as co-crystallized ligand).
A total of nine important chemical classes of PfDHODH inhibitors are reported
in the literature. Out of these triazolopyrimidine derivatives and N-alkyl-5benzimidazole thiophene-2-carboxamide analogs were found to be most suitable
with IC 50 values in lower nanomolar range. The SBDD approach is facilitated in the
designing of lead molecules with optimal in vitro and in vivo activity, good
metabolic profile with minimum toxicity along with selectivity against HsDHODH.
DSM265 has been is under clinical development and Genz-669178 is understudy
for clinical trials suitability. Various in silico studies are also reported which mainly
include 3D-QSAR studies/molecular docking/molecular dynamics.
Acknowledgements The University Grants Commission is gratefully acknowledged for the
financial support to Shweta Bhagat (UGC, Grant No. 43395). The authors thank Department of
Science and Technology (DST), Government of India, New Delhi, India, for financial support.
References
1. World Malaria Report (2017) World Health Organization, Geneva. doi: ISBN
978-92-4-156552-3
2. [a] Gregson A, Plowe CV (2005) Mechanisms of resistance of malaria parasites to antifolates.
Pharmacol Rev 57:117–145; [b] Harinasuta T, Suntharasamai P, Viravan C (1965)
Chloroquine-resistant falciparum malaria in Thailand. The Lancet 2:657–660; [c]
Sirawaraporn W, Prapunwattana P et al. (1993) The dihydrofolate reductase domain of
Plasmodium falciparum thymidylate synthase-dihydrofolate reductase. Gene synthesis,
expression, and anti-folate-resistant mutants. J Biol Chem 268:21637–21644
3. Wells TNC, van Huijsduijnen RH, Van Voorhis WC (2015) Malaria medicines: a glass half
full? Nat Rev Drug Discov 14:424–442
4. Tinto H, D’Alessandro U et al (2015) Efficacy and safety of RTS, S/AS01 malaria vaccine
with or without a booster dose in infants and children in Africa: final results of a phase 3,
individually randomised, controlled trial. The Lancet 386:31–45
5. Anderson AC (2003) The process of structure-based drug design. Chem Biol 10:787–797
Structure-Based Design of PfDHODH Inhibitors …
215