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Pulung, Maria Ludya
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Agriculture, Biological Sciences & Forestry Biochemistry, Genetics & Molecular Biology Chemical Engineering, Chemistry & Bioengineering Chemistry Energy Environmental Science Immunology & microbiology Materials Science & Nanotechnology Mathematics Physics

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Investigation of New 4-Benzyloxy-2-trichloromethylquinazoline Derivatives as Plasmodium falciparum Dihydrofolate Reductase-thymidylate Synthase Inhibitors: QSAR, ADME, Drug-likeness, Toxicity, Molecular Docking and Molecular Dynamics Simulation Yogaswara, Radite; Pranowo, Harno Dwi; Prasetyo, Niko; Pulung, Maria Ludya
Journal of Multidisciplinary Applied Natural Science Vol. 5 No. 2 (2025): Journal of Multidisciplinary Applied Natural Science
Publisher : Pandawa Institute

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.47352/jmans.2774-3047.258

Abstract

Plasmonium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is one of the most crucial antimalarial targets. Mutations in the binding pocket of this target lead to resistance to the antifolate. The mutations influence the amino acid residues at points 51, 59, 108 and 164 and contribute significantly to malaria not being treated well. Priority should therefore be given to the development of antifolate-resistance drugs. These studies aim to investigate new 4-benzyloxy-2-trichloromethylquinazoline derivatives as PfDHFR-TS inhibitors using QSAR, ADME, drug-likeness, toxicity, molecular docking studies, and molecular dynamics simulations. The best equation model from the QSAR analysis used MLR and PLS statistics to show that the pIC50 is linearly related to GATS4e, SpMax AEA(ed), and Mor28e, but inverted when compared to ATS6m and ATSC7m. The predictive ability of the model was confirmed by internal and external validation. In addition, the Y-randomization validation showed that the QSAR model was reliable, robust, and stable, with a cRp2 score of over 0.5. ADME and drug-likeness predictions confirmed the new QSAR design for molecules S10, S23 and S64. Based on the toxicity results, three molecules are expected to have moderate and non-toxic properties, starting with S23 and then S10 and S64. Molecular docking studies show that all three molecules have high binding energies, 9.869, 9.589, and 9.565 kcal/mol. The amino acid residues Leu46, Asp54, Ser111, and Thr185 play a major role in ligand-receptor interaction in the binding pocket of quadruple mutant PfDHFR-TS. Furthermore, an evaluation of molecular dynamics simulations of three complexes S10-3JSU, S23-3JSU and S64-3JSU demonstrated stable interactions over 100 ns.
Antiplasmodial and Metabolite Profiling of Hyrtios sp. Sponge Extract from Southeast Sulawesi Marine Using LC-HRMS, Molecular Docking, Pharmacokinetic, Drug-likeness, Toxicity, and Molecular Dynamics Simulation Pulung, Maria Ludya; Swasono, Respati Tri; Sholikhah, Eti Nurwening; Yogaswara, Radite; Primahana, Gian; Raharjo, Tri Joko
Journal of Multidisciplinary Applied Natural Science Vol. 5 No. 2 (2025): Journal of Multidisciplinary Applied Natural Science
Publisher : Pandawa Institute

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.47352/jmans.2774-3047.259

Abstract

Hyrtios sponge is known to possess alkaloid compounds that may exhibit in vitro activity against Plasmodium falciparum. The aim of this study was therefore to isolate and characterise the antiplasmodial active compounds of Hyrtios sp. Sponges collected from the island of Podang-Podang, South Sulawesi, Indonesia. In addition, the LC-HRMS analysis was performed on the active fractions of methanol and ethyl acetate extract to evaluate their antiplasmodial activity. We also validated the in silico antiplasmodial activity of PfDHFR-TS with molecular docking, pharmacokinetics, drug likeness, toxicity, and molecular dynamics analysis. The molecular docking studies showed that the synthesized extremes would have high binding affinity to PfDHFR-TS, thus confirming their potential as powerful enzyme inhibitors. Moreover, the pharmacokinetic and drug-likeness calculations showed that all compounds met the requirements for sufficient resistance and bioavailability, indicating potential as therapeutic candidates. The results of the toxicity analysis indicated that the compounds had a relatively good safety profile, but some potential adverse reactions in the renal and cardiac vasculature could not be excluded. Molecular dynamics simulations confirmed that the complexes formed between the ligand and the target were stable, and the low RMSD value indicated that the active site interactions were also quite stable. These observations reinforce the notion that the extract from Hyrtios sp. not only shows remarkable antimalarial activity but also exhibits pharmacological properties of a prospective drug candidate, which encourages further work in the development of malaria combination therapy both in clinical assessment and comprehensive mechanism of action investigation.
Co-Authors Eti Nurwening Sholikhah Harno Dwi Pranowo Prasetyo, Niko Primahana, Gian Respati Tri Swasono Tri Joko Raharjo Yogaswara, Radite