Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth

Sudha Rani Vippagunta, Arnulf Dorn, Hugues Matile, Apurba K. Bhattacharjee, Jean M. Karle, William Y. Ellis, Robert G. Ridley, Jonathan L Vennerstrom

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Abstract

Considerable data now support the hypothesis that chloroquine (CQ)- hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin μ-oxo dimers in a cofacial π-π sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 105 M-1 compared to 4.0 x 105 M-1 for CQ. Remarkably, we were not able to measure any significant interaction between hematin μ-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin μ-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable π-π interaction observed in the CQ-hematin μ-oxo dimer complex derives from a favorable alignment of the out-of-plane π-electron density in CQ and hematin μ-oxo dimer at the points of intermolecular contact. For 4- aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC50 values suggests that other properties of the CQ-hematin μ-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin μ-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.

Original languageEnglish (US)
Pages (from-to)4630-4639
Number of pages10
JournalJournal of Medicinal Chemistry
Volume42
Issue number22
DOIs
StatePublished - Nov 4 1999

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Hemin
Chloroquine
Polymerization
Parasites
Growth
Dimers
Inhibitory Concentration 50
Electrons
Calorimetry
Molecular modeling
Chlorine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. / Vippagunta, Sudha Rani; Dorn, Arnulf; Matile, Hugues; Bhattacharjee, Apurba K.; Karle, Jean M.; Ellis, William Y.; Ridley, Robert G.; Vennerstrom, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 42, No. 22, 04.11.1999, p. 4630-4639.

Research output: Contribution to journalArticle

Vippagunta, Sudha Rani ; Dorn, Arnulf ; Matile, Hugues ; Bhattacharjee, Apurba K. ; Karle, Jean M. ; Ellis, William Y. ; Ridley, Robert G. ; Vennerstrom, Jonathan L. / Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. In: Journal of Medicinal Chemistry. 1999 ; Vol. 42, No. 22. pp. 4630-4639.
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abstract = "Considerable data now support the hypothesis that chloroquine (CQ)- hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin μ-oxo dimers in a cofacial π-π sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 105 M-1 compared to 4.0 x 105 M-1 for CQ. Remarkably, we were not able to measure any significant interaction between hematin μ-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin μ-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable π-π interaction observed in the CQ-hematin μ-oxo dimer complex derives from a favorable alignment of the out-of-plane π-electron density in CQ and hematin μ-oxo dimer at the points of intermolecular contact. For 4- aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC50 values suggests that other properties of the CQ-hematin μ-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin μ-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.",
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AU - Vippagunta, Sudha Rani

AU - Dorn, Arnulf

AU - Matile, Hugues

AU - Bhattacharjee, Apurba K.

AU - Karle, Jean M.

AU - Ellis, William Y.

AU - Ridley, Robert G.

AU - Vennerstrom, Jonathan L

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N2 - Considerable data now support the hypothesis that chloroquine (CQ)- hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin μ-oxo dimers in a cofacial π-π sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 105 M-1 compared to 4.0 x 105 M-1 for CQ. Remarkably, we were not able to measure any significant interaction between hematin μ-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin μ-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable π-π interaction observed in the CQ-hematin μ-oxo dimer complex derives from a favorable alignment of the out-of-plane π-electron density in CQ and hematin μ-oxo dimer at the points of intermolecular contact. For 4- aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC50 values suggests that other properties of the CQ-hematin μ-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin μ-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.

AB - Considerable data now support the hypothesis that chloroquine (CQ)- hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin μ-oxo dimers in a cofacial π-π sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 105 M-1 compared to 4.0 x 105 M-1 for CQ. Remarkably, we were not able to measure any significant interaction between hematin μ-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin μ-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable π-π interaction observed in the CQ-hematin μ-oxo dimer complex derives from a favorable alignment of the out-of-plane π-electron density in CQ and hematin μ-oxo dimer at the points of intermolecular contact. For 4- aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC50 values suggests that other properties of the CQ-hematin μ-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC50 values were normalized for hematin μ-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.

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