ABSTRACT: Monopolar spindle 1 (Mps1), a dual-specific kinase, is related to the proper execution of chromosome biorientation and mitotic checkpoint signaling. The overexpression of Mps1 promotes the occurrence of cancer or the survival of aneuploid cancer cells, in other words, the reduction of Mps1 will severely reduce the viability of human cancer cells. Therefore, Mps1 is a potential target for cancer treatment. Recently, a series of novel pyrido [3,4-d] pyrimidine derivatives targeting Mps1 with high biological activity were synthesized. The crystal structure of Mps1 in complex with pyrido [3,4-d] pyrimidine derivatives was also reported, but there were no specific mechanism studies for this series of small molecule inhibitors. In this study, complexes binding modes were probed by molecular docking and further validated by molecular dynamics simulations and the molecular mechanics/generalized Born surface area (MM/GBSA) method. The results indicated that the van der Waals interactions and the nonpolar solvation energies were responsible to the basis for favorable binding free energies, all inhibitors interacted with residues I531, V539, M602, C604, N606, I607, L654, I663, and P673 of Mps1. By analyzing the hydrogen bonds, we found the residues G605 and K529 in Mps1 formed stable hydrogen bonds with compounds, it was more conducive to activities of Mps1 inhibitors. According to the above analysis, we further designed five new compounds. We found that compounds IV and V were better potential Mps1 inhibitors through docking and ADMET prediction. The obtained new insights not only were helpful in understanding the binding mode of inhibitors in Mps1, but also provided important references for further rational design of Mps1 inhibitors.
