What question did this study set out to answer?

The research aims to design and evaluate new Pf DHODH inhibitors to combat malaria by disrupting nucleotide synthesis.

March 21, 2026Letters in Drug Design & Discovery1 citationsOpen Access

Rational design of novel 2-aminopyrido3,4-dpyrimidin-4-one derivatives as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors using 3D QSAR, docking, molecular dynamics simulation approaches

SBShaival Bhatt BPBharat Patel APAshna Patel

Key Points

The research aims to design and evaluate new Pf DHODH inhibitors to combat malaria by disrupting nucleotide synthesis.
Developed 3D QSAR models using a dataset of 75 inhibitors.
Conducted PLS analysis and generated contour maps for compound design.
Performed molecular docking with AutoDock Vina on Pf DHODH crystal structure.
Carried out in silico ADMET predictions for drug-likeness assessment.
Evaluated the top compound's stability via molecular dynamics simulations for 200 ns.
The 3D QSAR model exhibited high reliability with R2 of 0.9 and Q2 of 0.805.
Designed compounds displayed moderate activity with pIC50 values between 7.3 and 7.741.
Compound 2d showed the best docking score of -9.541 kcal/mol and significant interaction similarities to a reference inhibitor.
Molecular dynamics confirmed good stability of the compound 2d with Pf DHODH over 200 ns.

Abstract

Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway and a validated antimalarial drug target. Inhibition of Pf DHODH enzyme disrupts nucleotide synthesis, which leads to parasite death. Field-based 3D QSAR models were developed using a dataset of 75 Pf DHODH inhibitors to identify key features interacting with the active site of the enzyme. Partial least squares (PLS) analysis was performed, and contour-map interpretation guided the design of new 2-aminopyrido3, 4- d pyrimidin-4-one derivatives. The activity (pIC 50) values of designed compounds were predicted using the PLS model-5. Drug-likeness and pharmacokinetic profiles of the designed compounds were evaluated through in silico ADMET prediction study. Molecular docking studies were performed for the designed compounds using AutoDock Vina 1. 2. 7 with the Pf DHODH crystal structure. Further, the compound with the best docking score was evaluated for stability using 200 ns molecular dynamics simulations and MM/GBSA calculations with gmxMMPBSA tools. The 3D QSAR model exhibited good statistical reliability with R 2 of 0. 9 and Q 2 of 0. 805. The generated contour maps were used for the design of new 2-aminopyrido3, 4- d pyrimidin-4-one derivatives. These analogues showed moderate predictive activity (pIC 50) in the range of 7. 3–7. 741. In silico ADMET evaluation showed that the designed molecule has acceptable drug-likeness and pharmacokinetic profiles. Docking studies revealed that compound 2d showed the highest docking score (-9. 541 kcal/mol) and formed key interactions similar to those observed in the reference inhibitor DSM265 (-9. 326 kcal/mol). MD simulation studies confirmed that compound 2d showed good stability of the complex with Pf DHODH over the 200 ns trajectory and with MM/GBSA calculations. These results suggest that the designed compounds have the potential to act as Pf DHODH inhibitors and antimalarial agents. A novel series of 2-aminopyrido3, 4- d pyrimidin-4-one will be synthesized and further evaluated experimentally for Pf DHODH inhibition and antimalarial activity.

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