QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR.
Ginkgolides, isolated from ginkgo balba leaves, were found to be powerful as natural antagonists of human platelet activating factor (PAF) in treatment of some diseases such as acute inflammation, tissue rejection, asthma, and ischemic injury. Ginkgolides have a cage skeleton consisting of six five-membered rings, therefore, are very tough to be synthesized. For finding new powerful substitutes of the natural ginkgolides for treating those diseases, three methods, viz. CoMFA, CoMSIA, and HQSAR, were used to investigate the relationship between 117 ginkgolide analogues with great structural diversity and their bioactivities against PAF receptor. The high q2 released from the different QSAR methods, ranging from 0.583 to 0.684, suggests that three rational and predictive QSAR models were successfully built. These models also show clearly how steric, electrostatic, hydrophobicity, and individual atom affect molecular bioactivity as antagonists of PAF. These results could also be used to account for the unusually higher bioactivity of ginkgolide B than other ginkgolides. The possible binding mechanism between ginkgolides and human PAF receptor was also deduced based on the QSAR models. Therefore, this study should be very helpful in discovering new drugs as PAF antagonists in fighting against various diseases related to PAF and PAF receptor.
Zhu
Weiliang
W
Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Pudong, Shanghai, PR China.
Chen
Gang
G
Hu
Lihong
L
Luo
Xiaomin
X
Gui
Chunshan
C
Luo
Cheng
C
Puah
Chum Mok
CM
Chen
Kaixian
K
Jiang
Hualiang
H
D046934:Ginkgolides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D046934:Ginkgolides; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor