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<p>An integrated computational strategy combining molecular docking, molecular dynamics (MD) simulations, MMGBSA binding free-energy calculations, and ADMET prediction was employed to investigate the inhibitory potential of cystodytins A–K against TGFβR1. The docking workflow was validated by re-docking the co-crystallized ligand QMY, achieving excellent agreement with the experimental structure (RMSD = 0.101 Å). Docking results revealed consistently favorable binding affinities across the cystodytin series, with cystodytin D (4), followed by cystodytins F (6) and G (7), ranking highest and displaying affinities comparable to the reference ligand. Key interactions were primarily mediated by hydrogen bonding with Tyr249 and Asp351, supported by extensive hydrophobic contacts within the ATP-binding cleft. Subsequent 500 ns MD simulations confirmed the dynamic stability of the selected TGFβR1–ligand complexes, as evidenced by stable RMSD, RMSF, and compact protein conformations. MMGBSA analysis indicated strongly favorable binding free energies, with compound 6 exhibiting the most stable binding dominated by van der Waals interactions. In silico ADMET evaluation suggested acceptable drug-likeness and favorable oral absorption, particularly for compounds 6 and 7. These findings highlight cystodytins F and G as promising scaffolds for TGFβR1 inhibition and warrant further experimental investigation.</p>

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In silico evaluation of cystodytins A–K targeting TGFβR1: integrated molecular docking, molecular dynamics simulations, and ADMET prediction

  • 期刊论文

  • 发表日期：

    2026年3月9日

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  • Nguyen Xuan Vu,
  • Bui Quoc Hung,
  • Hoang Thi Tue Trang,
  • Nguyen Xuan Ha

摘要

An integrated computational strategy combining molecular docking, molecular dynamics (MD) simulations, MMGBSA binding free-energy calculations, and ADMET prediction was employed to investigate the inhibitory potential of cystodytins A–K against TGFβR1. The docking workflow was validated by re-docking the co-crystallized ligand QMY, achieving excellent agreement with the experimental structure (RMSD = 0.101 Å). Docking results revealed consistently favorable binding affinities across the cystodytin series, with cystodytin D (4), followed by cystodytins F (6) and G (7), ranking highest and displaying affinities comparable to the reference ligand. Key interactions were primarily mediated by hydrogen bonding with Tyr249 and Asp351, supported by extensive hydrophobic contacts within the ATP-binding cleft. Subsequent 500 ns MD simulations confirmed the dynamic stability of the selected TGFβR1–ligand complexes, as evidenced by stable RMSD, RMSF, and compact protein conformations. MMGBSA analysis indicated strongly favorable binding free energies, with compound 6 exhibiting the most stable binding dominated by van der Waals interactions. In silico ADMET evaluation suggested acceptable drug-likeness and favorable oral absorption, particularly for compounds 6 and 7. These findings highlight cystodytins F and G as promising scaffolds for TGFβR1 inhibition and warrant further experimental investigation.