Abstract

Monopolar spindle 1 (Mps1), a crucial component of spindle assembly checkpoint, essential to maintain the chromosomal stability, is an attractive cancer drug target. Now the accessibility to multiple crystal structures of Mps1 ligand complexes and inhibitors with known biological activities have accelerated the identification of novel molecular scaffolds by means of computer. In this paper, we developed the structure-based and ligand-based phormacophores, and the two approaches were cascaded together for comparative analysis. The multiple pharmacophore models were evaluated using enrichment analysis. Then the six models were used for virtual screening of chemical databases. The retrieved compounds with novel scaffolds and good fitness were further refined by docking studies and ADME profiling. Finally, 16 hits were identified and the binding modes observed through docking the hits to the ATP binding domain gave valuable insights into the relationship between structural features and inhibitory activity. The present research work provides valuable information for rational design of potent and selective Mps1 agents.

Keywords: Monopolar spindle 1, pharmacophore modeling, 3D-QSAR, virtual screening, molecular docking, ADME profiling.

Graphical Abstract