Conformationally constrained analogues of diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C.
Diacylglycerol (DAG) lactones with altered functionality (C=O --> CH(2) or C=O --> C=S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.
Kang
Ji-Hye
JH
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Peach
Megan L
ML
Pu
Yongmei
Y
Lewin
Nancy E
NE
Nicklaus
Marc C
MC
Blumberg
Peter M
PM
Marquez
Victor E
VE
D001665:Binding Sites; D004075:Diglycerides / Q000138:chemical synthesis / Q000737:chemistry*; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry*; D008968:Molecular Conformation; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D013237:Stereoisomerism; D013816:Thermodynamics
D004075:Diglycerides; D007783:Lactones; D011493:Protein Kinase C