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

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.