Pharmacophore modeling and virtual screening for designing potential PLK1 inhibitors

Pharmacophore model of PLK1 inhibitors was established. This model was then used as a 3D query to screen several chemical databases including Specs, NCI, Maybridge, and CNPD. Pharmacophore models of Polo-like kinase-1 (PLK1) inhibitors have been established by using the HipHop and HypoGen algorithms...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-09, Vol.18 (18), p.4972-4977
Main Authors: Wang, Hui-Yuan, Cao, Zhi-Xing, Li, Lin-Li, Jiang, Pei-Du, Zhao, Ying-Lan, Luo, Shi-Dong, Yang, Li, Wei, Yu-Quan, Yang, Sheng-Yong
Format: Article
Language:English
Subjects:
Algorithms
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Cell Cycle Proteins - antagonists & inhibitors
Drug Design
Drug Evaluation, Preclinical - methods
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Heterocyclic Compounds - chemical synthesis
Heterocyclic Compounds - chemistry
Heterocyclic Compounds - pharmacology
Inhibitory Concentration 50
Kinase inhibitor
Medical sciences
Miscellaneous
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Pharmacophore modeling
Polo-Like Kinase 1
Protein Serine-Threonine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - antagonists & inhibitors
Structure-Activity Relationship
Transferases
Virtual screening
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Summary:Pharmacophore model of PLK1 inhibitors was established. This model was then used as a 3D query to screen several chemical databases including Specs, NCI, Maybridge, and CNPD. Pharmacophore models of Polo-like kinase-1 (PLK1) inhibitors have been established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9895), consists of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic feature, and one hydrophobic aliphatic feature. Hypo1 was further validated by test set and cross validation method. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge, and Chinese Nature Product Database (CNPD). The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally, a total of 20 compounds were selected and have been shifted to in vitro and in vivo studies. As far as we know, this is the first report on the pharmacophore modeling even the first publicly reported virtual screening study of PLK1 inhibitors.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2008.08.033