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In silico evaluation of cystodytins A-K targeting TGFβR1: integrated molecular docking, molecular dynamics simulations, and ADMET prediction
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DOI：10.1007/s13738-026-03392-3.png)
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Abstract
En 中文
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 TGF beta R1. The docking workflow was validated by re-docking the co-crystallized ligand QMY, achieving excellent agreement with the experimental structure (RMSD = 0.101 & Aring;). 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 TGF beta R1-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 TGF beta R1 inhibition and warrant further experimental investigation.
Keywords:
TETRACYCLIC AROMATIC ALKALOIDS
BETA
INHIBITOR
DISCOVERY
POTENT
WEB
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2.3
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138
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