title: Differential binding modes of diacylglycerol (DAG) and DAG lactones to protein kinase C (PK-C).
abstract: Diacylglycerol lactones (DAG lactones), analogous to highly potent diacylglycerols (DAGs) were synthesized to demonstrate the ability of PK-C to discriminate between two differential binding modes, sn-1 and sn-2. While both sn-1 and sn-2 binding modes are allowable in terms of hydrogen bonding, it has been found that in general, DAGs prefer to bind sn-1, while the corresponding analogous DAG lactones prefer to bind sn-2. However, this binding orientation can be directly influenced by the disposition and nature of the acyl substituent, particularly if it is highly branched. When the "binding driving force" (i.e., the larger branched acyl chain) is in the sn-2 position, a dramatic increase in binding affinity is observed in the DAG lactone as compared to its open chain DAG counterpart. As these analogous DAGs and DAG lactones have almost identical log P values, this difference in binding affinity is a direct result of the entropic advantage of constraining the glycerol backbone.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Dina M
authors.initials: DM
authors.lastname: Sigano
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Kassoum
authors.initials: K
authors.lastname: Nacro
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Marc C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: D004075:Diglycerides / Q000737:chemistry*; D006860:Hydrogen Bonding; D007783:Lactones / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004075:Diglycerides; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C