Quinazolinone Derivatives as Targeting pfDHFR and pfDHODH Inhibitor: In Silico Studies Using Molecular Docking, Molecular Dynamics Simulations, MM-PBSA, and ADMET Analysis
DOI:
https://doi.org/10.48048/tis.2026.11331Keywords:
Antimalarial, Quinazolinones, Molecular docking, Molecular dynamics, ADMET, Antimalarial, pfDHFR, pfDHODH, Quinazolinone, Molecular docking, Molecular dynamics, MM-PBSA, RAM, ADMETAbstract
Malaria remains a significant global health concern, with rising resistance to current antimalarial drugs. pfDHFR (Plasmodium falciparum Dihydrofolate Reductase) and pfDHODH (Plasmodium falciparum Dihydroorotate Dehydrogenase) are critical enzymes for parasite survival and have emerged as promising targets for drug development. Quinazolinones have shown potential as antimalarial agents due to their diverse pharmacological activities. This study aims to evaluate quinazolinones as potential inhibitors of pfDHFR and pfDHODH using molecular docking, molecular dynamics simulations, and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profiling to identify optimal candidates with improved efficacy and pharmacokinetics. Thirty quinazolinone derivatives were subjected to molecular docking against pfDHFR and pfDHODH to assess binding affinity and interaction modes. Promising compounds were further analyzed through molecular dynamics simulations to evaluate complex stability. Additionally, ADMET profiling was conducted to predict pharmacokinetic properties and toxicity. Molecular docking identified compounds 3, 5, and 12 as promising pfDHFR inhibitors, with compound 3 exhibiting the most favorable binding energy. For pfDHODH, compounds 2, 11, and 20 showed strong interactions. Molecular dynamics simulations confirmed the stability of these complexes, with compounds 3 and 5 being stable against pfDHFR and compounds 20 and 11 against pfDHODH. ADMET analysis revealed favorable drug-like properties for these compounds, although some toxicity concerns were noted. This study demonstrates the potential of quinazolinone derivatives as next-generation antimalarial agents targeting pfDHFR and pfDHODH. Compounds 3, 5, 11, and 12 are identified as promising candidates due to their strong binding affinities and stable pharmacokinetic profiles. Further optimization and experimental validation are necessary to develop these compounds into effective therapeutic agents against malaria.
HIGHLIGHTS
- Thirty quinazolinone derivatives were designed and examined as potential inhibitors of pfDHFR and pfDHODH through molecular docking and dynamic simulations.
- C-Arylquinazolinones bearing hydroxyl groups were the most potential candidates.
- The ADMET results showed that the quinazolinones exhibited no potential toxicity.
GRAPHICAL ABSTRACT
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