Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer

Abstract

The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology.

Keywords: Mps1; bioinformatics; cancer; flavonoid-like compounds; molecular docking; poor prognosis tumours.

Figure 1

Structure of Mps1 kinase domain (PDB ID 5ljj).

Figure 2

Reversine can establish polar interactions with the Mps1 kinase domain.

Figure 3

Cartoon showing the structure of the Mps1 kinase–68916574 small compound complex. The latter molecule is shown in grey (XP GScore −9.3 kcal/mol). H-bond interactions between 68916574 and the Mps1 residue Gly605 are shown in yellow dashed lines.

Figure 4

Comparison of the chemical structures of the isoflavones daidzein, fisetin, genistein, and glycitein and the Mps1 inhibitor reversine.

Figure 5

Details of the interaction between the human Mps1 kinase domain and reversine (grey) (PDB ID 5ljj) and its comparison with the anticipated mode of binding to Mps1 of the flavonoids fisetin (pink), genistein (green), daidzein (yellow), and glycitein (orange) as predicted by molecular docking. H-bond interactions are shown in yellow dashed lines. Details of these interactions are also shown in Supplementary Figure S1b–d, respectively.

Figure 6

Structural diversity of new isoflavoids as potential Mps1 kinase inhibitors. The number in brackets corresponds to the Glide score.

Figure 7

Molecular docking of the top selected isoflavonid, the compound 5378180, to human Mps1 kinase domain (PDB ID 5ljj). The protein is shown in cartoon representation and the compound 5378180 in stick-ball representation. H-bond interactions are shown in yellow dashed lines (Gly605, Asp608, Ala651, Gln672, Ileu663 and Lys553). The Glide score of this interaction was −14.5 kcal/mol.