3D QSAR Studies of Mps1 (TTK) Kinase Inhibitors Based on CoMFA

Abstract

Monopolar spindle 1 (Mps1) is an attractive cancer target due to its high expression levels in a wide range of cancer cells. Mps1 is a dual specificity kinase. It plays an essential role in mitosis. The high expression od Mps1 was observed in various grades of breast cancers. In the current study, we have developed a CoMFA model of pyridazine derivatives as Mps1 kinase inhibitors. The developed CoMFA model ($q^2=0.797$ 수식 이미지; ONC=6; $r^2=0.992$ 수식 이미지) exhibited a good predictive ability. The model was then validated by Leave out five, progressive sampling and bootstrapping and found to be robust. The analysis of the CoMFA contour maps depicted favorable and unfavorable regions to enhance the activity. Bulky positive substitution at $R^3$ 수식 이미지 position and Negative substitution in $R^1$ 수식 이미지 position is favored could increase the activity. In contrast, bulky substitution in $R^1$ 수식 이미지 position is not favored. Our results can be used in designing a potent Mps1 (TTK) inhibitor.