Molecular models of N-Benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-δ

J. B. Roaten, M. G. Kazanietz, T. W. Sweatman, Leonard Lothstein, M. Israel, A. L. Parrill

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline with experimental antitumor activity superior to that of doxorubicin (DOX). AD 198, unlike DOX, only weakly binds DNA, is a poor inhibitor of topoisomerase II, and circumvents anthracycline-resistance mechanisms, suggesting a unique mechanism of action for this novel analogue. The phorbol ester receptors, protein kinase C (PKC) and β2-chimaerin, were recently identified as selective targets for AD 198 in vitro. In vitro, AD 198 competes with [ 3H]PDBu for binding to a peptide containing the isolated C1b domain of PKC-δ (δC1b domain). In the present study molecular modeling is used to investigate the interaction of AD 198 with the δC1b domain. Three models are identified wherein AD 198 binds into the groove formed between amino acid residues 6-13 and 21-27 of the δC1b domain in a manner similar to that reported for phorbol-13-acetate and other ligands of the C1 domain. Two of the identified models are consistent with previous experimental data demonstrating the importance of the 14-valerate side chain of AD 198 in binding to the C1 domain as well as current data demonstrating that translocation of PKC-α to the membrane requires the 14-valerate substituent. In this regard, the carbonyl of the 14-valerate participates in hydrogen bonding to the δC1b while the acyl chain is positioned for stabilization of the membrane-bound protein-ligand complex in a manner analogous to the acyl chains of the phorbol esters. These studies provide a structural basis for the interaction of AD 198 with the δC1b domain and a starting point for the rational design of potential new drugs targeting PKC and other proteins with C1 domains.

Original languageEnglish (US)
Pages (from-to)1028-1034
Number of pages7
JournalJournal of Medicinal Chemistry
Volume44
Issue number7
DOIs
StatePublished - Mar 29 2001

Fingerprint

Molecular Models
Phorbol Esters
Protein Kinase C
Valerates
Anthracyclines
Doxorubicin
Topoisomerase II Inhibitors
Ligands
Membranes
N-benzyladriamycin-14-valerate
Molecular modeling
Hydrogen Bonding
Drug Delivery Systems
Hydrogen bonds
Membrane Proteins
Proteins
Acetates
Stabilization
Amino Acids
Peptides

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

Molecular models of N-Benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-δ. / Roaten, J. B.; Kazanietz, M. G.; Sweatman, T. W.; Lothstein, Leonard; Israel, M.; Parrill, A. L.

In: Journal of Medicinal Chemistry, Vol. 44, No. 7, 29.03.2001, p. 1028-1034.

Research output: Contribution to journalArticle

Roaten, J. B. ; Kazanietz, M. G. ; Sweatman, T. W. ; Lothstein, Leonard ; Israel, M. ; Parrill, A. L. / Molecular models of N-Benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-δ. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 7. pp. 1028-1034.
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abstract = "N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline with experimental antitumor activity superior to that of doxorubicin (DOX). AD 198, unlike DOX, only weakly binds DNA, is a poor inhibitor of topoisomerase II, and circumvents anthracycline-resistance mechanisms, suggesting a unique mechanism of action for this novel analogue. The phorbol ester receptors, protein kinase C (PKC) and β2-chimaerin, were recently identified as selective targets for AD 198 in vitro. In vitro, AD 198 competes with [ 3H]PDBu for binding to a peptide containing the isolated C1b domain of PKC-δ (δC1b domain). In the present study molecular modeling is used to investigate the interaction of AD 198 with the δC1b domain. Three models are identified wherein AD 198 binds into the groove formed between amino acid residues 6-13 and 21-27 of the δC1b domain in a manner similar to that reported for phorbol-13-acetate and other ligands of the C1 domain. Two of the identified models are consistent with previous experimental data demonstrating the importance of the 14-valerate side chain of AD 198 in binding to the C1 domain as well as current data demonstrating that translocation of PKC-α to the membrane requires the 14-valerate substituent. In this regard, the carbonyl of the 14-valerate participates in hydrogen bonding to the δC1b while the acyl chain is positioned for stabilization of the membrane-bound protein-ligand complex in a manner analogous to the acyl chains of the phorbol esters. These studies provide a structural basis for the interaction of AD 198 with the δC1b domain and a starting point for the rational design of potential new drugs targeting PKC and other proteins with C1 domains.",
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AU - Kazanietz, M. G.

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AU - Lothstein, Leonard

AU - Israel, M.

AU - Parrill, A. L.

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AB - N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline with experimental antitumor activity superior to that of doxorubicin (DOX). AD 198, unlike DOX, only weakly binds DNA, is a poor inhibitor of topoisomerase II, and circumvents anthracycline-resistance mechanisms, suggesting a unique mechanism of action for this novel analogue. The phorbol ester receptors, protein kinase C (PKC) and β2-chimaerin, were recently identified as selective targets for AD 198 in vitro. In vitro, AD 198 competes with [ 3H]PDBu for binding to a peptide containing the isolated C1b domain of PKC-δ (δC1b domain). In the present study molecular modeling is used to investigate the interaction of AD 198 with the δC1b domain. Three models are identified wherein AD 198 binds into the groove formed between amino acid residues 6-13 and 21-27 of the δC1b domain in a manner similar to that reported for phorbol-13-acetate and other ligands of the C1 domain. Two of the identified models are consistent with previous experimental data demonstrating the importance of the 14-valerate side chain of AD 198 in binding to the C1 domain as well as current data demonstrating that translocation of PKC-α to the membrane requires the 14-valerate substituent. In this regard, the carbonyl of the 14-valerate participates in hydrogen bonding to the δC1b while the acyl chain is positioned for stabilization of the membrane-bound protein-ligand complex in a manner analogous to the acyl chains of the phorbol esters. These studies provide a structural basis for the interaction of AD 198 with the δC1b domain and a starting point for the rational design of potential new drugs targeting PKC and other proteins with C1 domains.

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