Computer simulation of the binding of naphthyridinomycin and cyanocycline A to DNA.
Cyanocycline A was found to have a pKa of 6.6. Protonation of N14 was established by 1H NMR spectroscopy. In strongly acidic solution the oxazolidine ring opened irreversibly. A model was derived for the binding of naphthyridinomycin and cyanocycline A to the hexanucleotide duplex d(ATGCAT)2, by using the molecular mechanics and dynamics modules of AMBER 3.0. It involved protonation on the oxazolidine-ring nitrogen, reduction of the quinone ring to a hydroquinone, formation of an iminium ion with loss of the C7 substituent, noncovalent binding in the minor groove with the hydroquinone ring in the 3'-direction from guanine, and covalent binding to the 2-amino group of this guanine with C7 adopting the R configuration. This model is consistent with the experimental evidence on the DNA binding of these drugs. An alternative binding mode based on opening of the oxazolidine ring and alkylation at C3a also was feasible according to molecular mechanics calculations. The geometry of naphthyridinomycin does not permit interstrand cross-linking involving both C3a and C7, but formation of a cross-link to protein appears possible. When the covalent naphthyridinomycin-d(ATGCAT)2 models were refined in the presence of water and counterions, the models with the most favorable net binding enthalpies were the same as those produced by simulation in vacuum. Qualitative estimates of the relative entropy changes resulting from adduct formation were based on the number of ordered (hydrogen bonded) water molecules released from d(ATGCAT)2 and from the drug. In all cases but one, d(ATGCAT)2 loses five water molecules. It loses six in the C3a covalent model with 5',S geometry. Naphthyridinomycin hydroquinone loses up to two water molecules, depending on the particular adduct. The 3',R model was again favored for the C7 covalent adduct. Among the C3a covalent models, the one with 5',R geometry lost the second most water molecules, but it had the best binding enthalpy.
Hill
G C
GC
Department of Pharmaceutical Sciences, College of Pharmacy University of Arizona, Tucson 85721.
Wunz
T P
TP
MacKenzie
N E
NE
Gooley
P R
PR
Remers
W A
WA
D000478:Alkylation; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001483:Base Sequence; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009287:Naphthyridines / Q000378:metabolism; D009843:Oligoribonucleotides / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009287:Naphthyridines; D009843:Oligoribonucleotides; C069792:d(ATGCAT)2; C010752:naphthyridinomycin; C035070:cyanonaphthyridinomycin; D004247:DNA