Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Host-guest interactions can be modelled as a non-bonding recognition process using long-range electrostatic forces. By using molecular isopotential maps the differences between the methotrexate-dihydrofolate reductase and folate-dihydrofolate reductase complexes can be predicted. By extending the technique to molecule-molecule docking the interaction of formamide with the crown ether 18-crown-6 can be simulated with reasonable accuracy. The closely related problem of predicting the separation of enantiomers of chiral molecules by chromatography has been attempted with encouraging results. A preliminary report is presented on the progress being made towards a better model for simulating stacking arrangement of pi systems by charge distribution.
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PMID:Molecular modelling approaches to host-guest complexes. 193 24

The protonation energies of 2,4-diamino triazine, an inhibitor of the therapeutic target dihydrofolate reductase, has been calculated using ab initio (Hartree-Fock) calculations. It is found that N1 (see Fig. 1) exhibits the highest proton affinity (261.6 kcal/mol) by comparison with other inhibitor protonation sites. The energies of binding of the formate ion and formamide (as models for the amino acid residues in the active site of dihydrofolate reductase) to neutral and protonated 2,4-diamino triazine are also obtained. The highest binding energies are featured by the complex formed from a formate attached to the N4 and N1 protonated forms of the triazine. However, as N4 has a comparatively low proton affinity (195.0 kcal/mol), it is unlikely that an interaction of this nature would prevail. On the other hand, the formate-protonated N1 interaction is similar to the structures identified by X-ray crystallography of enzyme-triazine complexes.
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PMID:Ab initio studies of 2,4-diamino triazine and its complexes with ligands: a model for inhibitor-active site interactions of dihydrofolate reductase. 792 2

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx) are carcinogens found in cooked meats that form DNA adducts upon metabolic activation. Purified DNA from Chinese hamster ovary (CHO) cells was reacted in vitro with the active metabolites N-acetoxy-IQ or N-acetoxy-MelQx, and the adduct levels in the 5' dihydrofolate reductase (DHFR) gene and downstream region were quantitated by Southern hybridization. Adducted and restricted DNA was treated with Escherichia coli uvrABC excinuclease or alkali (0.1 N NaOH, 37 degrees C, 60 min) to incise DNA at IQ and MelQx adduct sites. The DNA was then denatured with formamide, electrophoresed on a neutral agarose gel, transferred to a support membrane, and hybridized with sequence-specific DNA probes. Both uvrABC and alkali reduced the intensity of Southern hybridization in proportion to the number of IQ or MelQx adducts in DNA, indicating that these adducts are substrates for uvrABC and that they form alkali-labile lesions in DNA. IQ and MelQx adduct levels were the same in the 5' DHFR gene and in the downstream region. Southern hybridization analysis of pBR322 containing known levels of IQ or MelQx adducts showed that the efficiency of cutting IQ or MelQx adducts by uvrABC excinuclease and alkali was approximately 30% and 15%, respectively. 32P-postlabeling studies examining adduct level in bulk DNA further showed that the adduct profiles were identical in pBR322, CHO DNA, and cultured CHO cells exposed to the reactive metabolites of IQ or MelQx. The results indicate that IQ and MelQx adducts can be quantitated in specific genomic sequences and that this method should be directly applicable to studies of gene-specific repair of these adducts in cultured cells.
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PMID:Quantitation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline DNA adducts in specific sequences using alkali or uvrABC excinuclease. 845 90