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Computational exploration of maternal embryonic leucine zipper kinase (MELK) as a cancer drug target.

ABSTRACT: Maternal embryonic leucine zipper kinase (MELK) is of vital importance due to its significant role in cancer development and its association with poor prognosis in different cancers. Here, we employed several computer aided drug design approaches to shortlist potential binding molecules of MELK. For virtual screening, asinex oncology library (containing 6334 drugs) and comprehensive marine natural products database (containing approximately 32,000 drugs) were used. The study identified two drug molecules: Top-2 and Top-3 as high affinity binding MELK molecules compared to the control co-crystalized Top-1 inhibitor. Both the shortlisted compounds and the control showed high stable binding free energy and high GOLD score. The compounds and control also reported stable dynamics with root mean square deviations (RMSD) value ∼ 2 Å in 500 ns. Similarly, the MELK active site residues were observed in good stability with the compounds. Further, it was noticed the compounds/control formed multiple hydrogen bonds with the MELK active pocket residues which is the main reason of high intermolecular stability. Atomic level binding free energies determined van der Waals and electrostatic energies to play vital role in stable complex formation. From drug likeness and pharmacokinetics perspective, the compounds are ideal molecules for further investigation. Overall, the results are promising and might be tested in in vivo and in vitro studies against MELK.

SUBMITTER: Makki Almansour N

PROVIDER: S-EPMC9235044 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT-qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair-related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

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Computational exploration of maternal embryonic leucine zipper kinase (MELK) as a cancer drug target.

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