Structure-based quantitative structure-activity relationship studies of checkpoint kinase 1 inhibitors.
Structure-based quantitative structure-activity relationship (QSAR) studies on a series of checkpoint kinase 1 (Chk1) inhibitors were performed to find the key structural features responsible for their inhibitory activity. Molecular docking was employed to explore the binding mode of all inhibitors at the active site of Chk1 and determine the active conformation for the QSAR studies. Ligand and structure-based descriptors incorporating the ligand-receptor interaction were generated based on the docked complex. Genetic Algorithm-Multiple Linear Regression (GA-MLR) method was used to build 2D QSAR model. The 2D QSAR model gave a squared correlation coefficient R(2) of 0.887, cross-validated Q(2) of 0.837 and the prediction squared correlation coefficient R(2)(pred) of 0.849, respectively. Furthermore, three-dimensional quantitative structure-activity relationship (3D QSAR) model using comparative molecular field analysis (CoMFA) with R(2) of 0.983, Q(2) of 0.550 and R(2)(pred) of 0.720 was also developed. The obtained results are helpful for the design of novel Chk1 inhibitors with improved activities.
Du
Juan
J
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
Xi
Lili
L
Lei
Beilei
B
Lu
Jing
J
Li
Jiazhong
J
Liu
Huanxiang
H
Yao
Xiaojun
X
D000465:Algorithms; D000071877:Checkpoint Kinase 1; D016014:Linear Models; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1