Computational molecular dynamics unveils polyphenolic luteolin and pedalitin as promising scaffolds targeting MPS1/TTK kinase for developing novel cancer therapeuticsNilay Singh, Ashutosh Pal, Deepak Rana, Promila Sharma, Ashish Thapliyal, and Debasis Mitra Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, India
E-mail: sneel726@gmail.com Abstract: The spindle assembly checkpoint (SAC) relies on the recruitment of monopolar spindle 1 (MPS1) kinase to kinetochores to ensure proper chromosome spindle attachments before anaphase. MPS1/TTK has emerged as a promising target for cancer therapy, highlighting the need for novel inhibitors with improved efficacy and reduced toxicity. This study explored the use of nature-derived polyphenols as potential inhibitors of MPS1/TTK kinase using in silico screening. Initially, 17 bioactive polyphenolic compounds with known kinase inhibitory activities were evaluated for drug-likeness based on Lipinski’s parameters. Molecular docking against the MPS1/TTK kinase was performed to assess the binding modes and energies in comparison to the known inhibitor BAY-1217389. Top hits with favourable docking scores were further analysed for ADME properties, bioactivity, molecular dynamics simulations, and binding free energy calculations. Through this comprehensive approach, two polyphenolic compounds, luteolin and pedalitin, were identified as promising inhibitors of MPS1 kinase. Molecular dynamics simulations revealed binding free energies of − 33.48 ± 1.08 kcal/mol and − 24.91 ± 2.70 kcal/mol for luteolin and Pedalitin, respectively. Principal component analysis demonstrated that the MPS1-Pedalitin complex explored a highly rigid conformational space, while the MPS1-luteolin complex exhibited greater structural flexibility and protein expansion. These findings suggest that luteolin and pedalitin possess favourable structural and pharmacological properties, making them promising compounds for the development of novel anti-cancer agents. These natural polyphenolic compounds warrant further experimental validation as potential candidates for anticancer drug development through the inhibition of mitotic MPS1/TTK kinase. This computational pipeline will pave the way for the identification of novel chemotypes targeting MPS1, potentially advancing targeted cancer treatment options. Full paper is available at www.springerlink.com. DOI: 10.1007/s11696-025-04488-5
Chemical Papers 80 (2) 1769–1802 (2026) |
Saturday, April 25, 2026 
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