Pharmacophore modeling study based on known spleen tyrosine kinase inhibitors together with virtual screening for identifying novel inhibitors.
In this investigation, chemical features based 3D pharmacophore models were developed based on the known inhibitors of Spleen tyrosine kinase (Syk) with the aid of hiphop and hyporefine modules within catalyst. The best quantitative pharmacophore model, Hypo1, was used as a 3D structural query for retrieving potential inhibitors from chemical 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 studies to refine the retrieved hits. Finally 30 compounds were selected from the top ranked hit compounds and conducted an in vitro kinase inhibitory assay. Six compounds showed a good inhibitory potency against Syk, which have been selected for further investigation.
Xie
Huan-Zhang
HZ
State Key Laboratory of Biotherapy, West China Hospital, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
Li
Lin-Li
LL
Ren
Ji-Xia
JX
Zou
Jun
J
Yang
Li
L
Wei
Yu-Quan
YQ
Yang
Sheng-Yong
SY
D003198:Computer Simulation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D012984:Software; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase