Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity.
Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere-Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.
a Department of Pharmaceutical Chemistry , Institute of Pharmacy, Nirma University , Ahmedabad , India.
V K
VK
Vyas
a Department of Pharmaceutical Chemistry , Institute of Pharmacy, Nirma University , Ahmedabad , India.
G
G
Qureshi
a Department of Pharmaceutical Chemistry , Institute of Pharmacy, Nirma University , Ahmedabad , India.
M
M
Ghate
b Institute of Science, Nirma University , Ahmedabad , India.
H
H
Patel
b Institute of Science, Nirma University , Ahmedabad , India.
S
S
Dalai
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use; D062126:Databases, Chemical; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D062105:Molecular Docking Simulation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship
D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors
GALAHAD; PfDHODH inhibitors; antimalarial agents; molecular docking; pharmacophore modelling; virtual screening