A specific pharmacophore model of Aurora B kinase inhibitors and virtual screening studies based on it.
In this study, 3D-pharmacophore models of Aurora B kinase inhibitors have been developed by using HipHop and HypoGen modules in Catalyst software package. The best pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9911), consists of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic aliphatic moiety and one ring aromatic feature. Hypo1 was validated by test set and cross-validation methods. And the specificity of Hypo1 to Aurora B inhibitors was examined with the use of selective inhibitors against Aurora B and its paralogue Aurora A. The results clearly indicate that Hypo1 can differentiate selective inhibitors of Aurora B from those of Aurora A, and the ring aromatic feature likely plays some important roles for the specificity of Hypo1. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD) for identifying new inhibitors of Aurora B. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies to refine the retrieved hits, and some compounds selected from the top ranked hits have been suggested for further experimental assay studies.
Wang
Hui-Yuan
HY
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
Li
Lin-Li
LL
Cao
Zhi-Xing
ZX
Luo
Shi-Dong
SD
Wei
Yu-Quan
YQ
Yang
Sheng-Yong
SY
D064107:Aurora Kinase B; D064127:Aurora Kinases; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015203:Reproducibility of Results; D012984:Software; D013329:Structure-Activity Relationship
C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases