The interaction of the heme-octapeptide, N-acetylmicroperoxidase-8 with antimalarial drugs: solution studies and modeling by molecular mechanics methods.
The equilibrium constants for the coordination of quinine (log K = 2.55 +/- 0.02) and 9-epiquinine (log K = 2.42 +/- 0.05) to form a 1:1 complex with the monomeric ferric hemeoctapeptide from cytochrome c, N-acetylmicroperoxidase-9 have been determined in aqueous solution (pH 6.25, 0.1 M phosphate buffer) at 25 degrees C. The electronic spectra of the complexes suggest that coordination to Fe(III) occurs through the 9-alkoxide group, in agreement with previous NMR work on the interaction of quinine with urohaemin-I [I. Constantinidis and J. D. Satterlee, J. Amer. Chem. Soc. 110, 927 (1988)]. By contrast, two chloroquine molecules bind sequentially to N-acetylmicroperoxidase-8 under the same conditions (log K1 = 3.08 +/- 0.04; log K2 = 1.56 +/- 0.10) in an apparently pi- pi cofacial manner. Molecular mechanics techniques have been applied to a study of the structure of these species with an Fe(III)-porphine nucleus, and show that coordination of the 9-alkoxide group to Fe(III) is possible for both quinine and 9-epiquine, with the quinoline ring system virtually parallel to the porphyrin plane. The energy-minimized structure for the interaction of a single chloroquine molecule with Fe(III)-porphine has the quinoline rings parallel to the periphery of the porphyrin ring.
Marques
H M
HM
Department of Chemistry, University of the Witwatersrand, Johannesburg, South Africa.
Voster
K
K
Egan
T J
TJ
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004347:Drug Interactions; D006420:Hemeproteins / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010544:Peroxidases / Q000737:chemistry / Q000494:pharmacology*; D011803:Quinine / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013053:Spectrophotometry; D013816:Thermodynamics
D000962:Antimalarials; D006420:Hemeproteins; D010446:Peptide Fragments; D012996:Solutions; D002738:Chloroquine; D011803:Quinine; C071067:N(alpha)-acetylmicroperoxidase-8; D010544:Peroxidases