Differential binding modes of diacylglycerol (DAG) and DAG lactones to protein kinase C (PK-C)

Dina M. Sigano, Megan L. Peach, Kassoum Nacro, Yongseok Choi, Nancy E. Lewin, Marc C. Nicklaus, Peter M. Blumberg, Victor E. Marquez

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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.

Original languageEnglish
Pages (from-to)1571-1579
Number of pages9
JournalJournal of Medicinal Chemistry
Volume46
Issue number9
DOIs
Publication statusPublished - 2003 Apr 24

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Sigano, D. M., Peach, M. L., Nacro, K., Choi, Y., Lewin, N. E., Nicklaus, M. C., Blumberg, P. M., & Marquez, V. E. (2003). Differential binding modes of diacylglycerol (DAG) and DAG lactones to protein kinase C (PK-C). Journal of Medicinal Chemistry, 46(9), 1571-1579. https://doi.org/10.1021/jm020476o