Characterization of Candida albicans Dihydrofolate Reductase

Baccanari, David P.; Tansik, Robert L.; Joyner, S S; Fling, Mary E.; Smith, Philip L.; Freisheim, James H.

doi:10.1016/s0021-9258(19)85059-7

Cited by 43 publications

(13 citation statements)

References 37 publications

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“…After some early cycles of simulated annealing refinement, structure optimization continued with molecular modelling alternating with cycles of restrained leastsquares refinement. For part of the region of lowest sequence homology between P. carinii and L1210 enzymes (residues 155-185) reference was made to the structure of Candida albicans DHFR [14] whose unpublished coordinates were made available to us (L Kuyper and M Whitlow, personal communication). It was noted that, of residues 169-185, 12 are identical or conservatively altered beween the two enzymes, and, accordingly, C. albicans DHFR coordinates were used to guide the modelling of these 17 residues into electron density.…”

Section: Resultsmentioning

confidence: 99%

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 å resolution

et al. 1994

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These structures show how two drugs interact with a fungal DHFR. A comparison of the three-dimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.

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Section: Resultsmentioning

confidence: 99%

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 å resolution

et al. 1994

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“…Biology. Dihydrofolate reductase from C. albicans was prepared as previously described 14 and assayed in 0.1 M imidazole chloride buffer (pH 6.4), with 70 µM NADPH and 45 µM dihydrofolate in a final volume of 1 mL at 30 °C. Recombinant human DHFR (from Anatrace, Maumee, OH) was assayed in 50 mM sodium phosphate, pH 7.0.…”

Section: N-cyano-n′-(2-methyl-1-(1-ethylpropyl)indol-5-yl)guanidine (...mentioning

confidence: 99%

“…One area of recent focus is the search for inhibitors of DHFR from various opportunistic organisms such as the protozoan parasite Toxoplasma gondii [11][12][13] and the fungus Candida albicans. 14 The importance of opportunistic diseases has risen considerably in recent years, owing to the large increase in the population of immunocompromised patients associated with the AIDS (acquired immune deficiency syndrome) epidemic, organ transplantation, and cancer chemotherapy. [15][16][17] Therapeutic intervention is limited by the dearth of safe and effective antiparasitic and antifungal agents.…”

Section: Introductionmentioning

confidence: 99%

High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size

et al. 1996

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A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K(i) values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.

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“…19 These compounds were designed based on the X-ray crystal structure of Candida albicans DHFR in complex with a PQZ derivative. 34 SAR studies indicated that alkyl substitutions at N 7 were indispensable to retain potent DHFR inhibitory activity. This was consistent with the binding mode that the N 7 substituent pointed toward a large hydrophobic pocket in DHFR.…”

Section: Pqzs As Dihydrofolate Reductase (Dhfr) Inhibitorsmentioning

confidence: 99%

The chemistry and pharmacology of privileged pyrroloquinazolines

Chao

Xiao

2015

Med. Chem. Commun.

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The advent of next-generation sequencing (NGS) technology has plummeted the cost of whole genome sequencing, which has provided a long list of putative drug targets for a variety of diseases ranging from infectious diseases to cancers. The majority of these drug targets are still awaiting high-quality small molecule ligands to validate their therapeutic potential and track their druggability. Screening compound libraries based on privileged scaffolds is an efficient strategy to identify potential ligands to distinct biological targets. 7H-Pyrrolo[3,2-f]quinazoline (PQZ) is a potential privileged heterocyclic scaffold with diverse pharmacological properties. A number of biological targets have been identified for different derivatives of PQZ. This review summarized the synthetic strategies to access the chemical space associated with PQZ and discussed their unique biological profiles.

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Characterization of Candida albicans Dihydrofolate Reductase

Cited by 43 publications

References 37 publications

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 å resolution

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 å resolution

High-Affinity Inhibitors of Dihydrofolate Reductase: Antimicrobial and Anticancer Activities of 7,8-Dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with Small Molecular Size

The chemistry and pharmacology of privileged pyrroloquinazolines

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