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<p>Drug-resistant <i>Plasmodium falciparum</i> has been on the rise, mainly due to point mutations in the pfDHFR or dihydrofolate reductase gene. This has heightened urgency to discover and develop new antimalarial drugs. This research utilized Pharmacophore Modeling, Virtual Screening, Molecular Docking and Molecular Dynamics Simulation techniques to identify potential pfDHFR inhibitors from virtual databases. Ligand-based pharmacophore hypothesis (H1) (r = 0.949, r<sup>2</sup> = 0.883) was formulated using a training set of 28 compounds that demonstrated pfDHFR inhibitory activity across four orders of magnitude. Additionally, a Structure-based Pharmacophore Hypothesis (P1) was derived from the ligand-binding site in the pfDHFR protein. The thoroughly validated hypotheses (H1 and P1) were then employed as 3D queries to screen compounds from the chemical database. These compounds were initially screened for drug-likeness and ADME/Tox properties before undergoing pharmacophore mapping. Pharmacophore mapping and docking analyses, followed by 200&#xa0;ns molecular dynamics simulations using a mutant pfDHFR model, identified three promising lead candidates from the TCM database. The top compound, ZINC70454408, exhibited the highest H Bond energy of −14.204&#xa0;kcal/mol and a predicted <i>Ki</i> of 0.04&#xa0;µM, maintaining structural stability with an average RMSD of 2.1&#xa0;Å throughout the simulation. Two additional compounds, ZINC04096650 and ZINC85631105, also exhibited strong binding energies (− 122.64 and − 118.92&#xa0;kcal/mol, respectively) and low predicted Ki values (&lt; 0.1&#xa0;µM), with stable RMSD values ranging between 2.0 and 2.4&#xa0;Å. These findings underscore ZINC70454408 as the most promising natural product-based pfDHFR inhibitor candidate and provide a compelling rationale for future experimental validation.</p>

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Computational exploration of natural product inhibitors against mutant Plasmodium falciparum DHFR through pharmacophore modeling, docking, and MD simulations

  • 期刊论文

  • 发表日期：

    2026年1月27日

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  • Dhrubajyoti Gogoi,
  • Barbi Gogoi,
  • Partha Pratim Dutta,
  • Jun Moni Kalita,
  • Ankita Khataniar,
  • Manash Pratim Sharma,
  • Jithendar Reddy Mandhadi,
  • Mayur Mausoom Phukan,
  • Akhilesh Kumar Verma

摘要

Drug-resistant Plasmodium falciparum has been on the rise, mainly due to point mutations in the pfDHFR or dihydrofolate reductase gene. This has heightened urgency to discover and develop new antimalarial drugs. This research utilized Pharmacophore Modeling, Virtual Screening, Molecular Docking and Molecular Dynamics Simulation techniques to identify potential pfDHFR inhibitors from virtual databases. Ligand-based pharmacophore hypothesis (H1) (r = 0.949, r2 = 0.883) was formulated using a training set of 28 compounds that demonstrated pfDHFR inhibitory activity across four orders of magnitude. Additionally, a Structure-based Pharmacophore Hypothesis (P1) was derived from the ligand-binding site in the pfDHFR protein. The thoroughly validated hypotheses (H1 and P1) were then employed as 3D queries to screen compounds from the chemical database. These compounds were initially screened for drug-likeness and ADME/Tox properties before undergoing pharmacophore mapping. Pharmacophore mapping and docking analyses, followed by 200 ns molecular dynamics simulations using a mutant pfDHFR model, identified three promising lead candidates from the TCM database. The top compound, ZINC70454408, exhibited the highest H Bond energy of −14.204 kcal/mol and a predicted Ki of 0.04 µM, maintaining structural stability with an average RMSD of 2.1 Å throughout the simulation. Two additional compounds, ZINC04096650 and ZINC85631105, also exhibited strong binding energies (− 122.64 and − 118.92 kcal/mol, respectively) and low predicted Ki values (< 0.1 µM), with stable RMSD values ranging between 2.0 and 2.4 Å. These findings underscore ZINC70454408 as the most promising natural product-based pfDHFR inhibitor candidate and provide a compelling rationale for future experimental validation.