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<p>Maternal embryonic leucine zipper kinase (MELK) is a promising therapeutic target in cancer due to its overexpression in aggressive tumors and role in cell survival, proliferation, and therapy resistance. No MELK inhibitors are currently FDA-approved, so identifying potential leads is necessary for therapeutic development. In this study, we employed a computational pipeline to identify natural compounds from the IMPPAT 2.0 database as potential MELK inhibitors. Virtual high-throughput screening of 11,406 phytochemicals against the MELK kinase domain (PDB ID: 5K00) identified 15 top hits with binding affinities ranging from − 10.9 to − 9.9&#xa0;kcal/mol. Subsequent ADMET evaluation prioritized two compounds, Moracin G and Isolonchocarpin, which demonstrated favorable pharmacokinetic profiles and no PAINS alerts. PASS analysis revealed their strong antineoplastic and kinase-inhibitory potential, with Pa values &gt; 0.5 for key activities. Molecular dynamics simulations for&#xa0;300 ns confirmed stable binding of these compounds to MELK’s ATP-binding site, with RMSD values ≤ 0.28&#xa0;nm and compact structural dynamics (<i>R</i>g ~ 1.94&#xa0;nm). Principal component analysis, free energy landscapes, and MM-PBSA analyses highlighted stable conformations and appreciable binding free energies in MELK-ligand complexes, suggesting enhanced stability. These findings position Moracin G and Isolonchocarpin as promising scaffolds for developing selective MELK inhibitors, offering a pathway to disrupt cancer cell survival and improve therapeutic outcomes, although experimental validation is still required.</p>

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Computational identification of Moracin G and Isolonchocarpin as potent MELK inhibitors for anticancer drug discovery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月6日

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  • Prathibha Prasad,
  • Azna Zuberi,
  • Areej Ali Alzahrani,
  • Mohd Shahnawaz Khan

摘要

Maternal embryonic leucine zipper kinase (MELK) is a promising therapeutic target in cancer due to its overexpression in aggressive tumors and role in cell survival, proliferation, and therapy resistance. No MELK inhibitors are currently FDA-approved, so identifying potential leads is necessary for therapeutic development. In this study, we employed a computational pipeline to identify natural compounds from the IMPPAT 2.0 database as potential MELK inhibitors. Virtual high-throughput screening of 11,406 phytochemicals against the MELK kinase domain (PDB ID: 5K00) identified 15 top hits with binding affinities ranging from − 10.9 to − 9.9 kcal/mol. Subsequent ADMET evaluation prioritized two compounds, Moracin G and Isolonchocarpin, which demonstrated favorable pharmacokinetic profiles and no PAINS alerts. PASS analysis revealed their strong antineoplastic and kinase-inhibitory potential, with Pa values > 0.5 for key activities. Molecular dynamics simulations for 300 ns confirmed stable binding of these compounds to MELK’s ATP-binding site, with RMSD values ≤ 0.28 nm and compact structural dynamics (Rg ~ 1.94 nm). Principal component analysis, free energy landscapes, and MM-PBSA analyses highlighted stable conformations and appreciable binding free energies in MELK-ligand complexes, suggesting enhanced stability. These findings position Moracin G and Isolonchocarpin as promising scaffolds for developing selective MELK inhibitors, offering a pathway to disrupt cancer cell survival and improve therapeutic outcomes, although experimental validation is still required.