Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 48, Issue 18, Pages 5738-5748Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm050352m
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Funding
- Intramural NIH HHS [Z01 BC006176-22] Funding Source: Medline
- NCI NIH HHS [N01CO12400, N01-CO-12400] Funding Source: Medline
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Diacylglycerol (DAG) lactones with altered functionality (C=O -> CH2 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 (Cl 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.
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