Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of
            <i>Cryptosporidium parvum</i>
            Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations

Nelson, Richard G.; Rosowsky, A.

doi:10.1128/aac.45.12.3293-3303.2001

Cited by 49 publications

(31 citation statements)

References 76 publications

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“…In vitro kinetic studies also suggested that M. tuberculosis DHFR might have a lower affinity to trimethoprim compared with the homologous enzymes in other bacteria. The IC 50 of M. tuberculosis DHFR inhibited by trimethoprim is approximately 100-fold higher than E. coli DHFR, and its k i is 20-fold higher than that of the M. smegmatis enzyme [74,78,83,84]. …”

Section: Antifolatesmentioning

confidence: 99%

Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

Wolff

Nguyen²

2012

Expert Review of Anti-infective Therapy

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Antifolates inhibit de novo folate biosynthesis, whereas ethionamide targets the mycolate synthetic pathway in Mycobacterium tuberculosis. These antibiotics are effective against M. tuberculosis but their use has been hampered by concerns over toxicity and low therapeutic indexes. With the increasing spread of drug-resistant forms, interest in using old drugs for tuberculosis treatment has been renewed. Specific inhibitors targeting resistance mechanisms could sensitize M. tuberculosis to these available, clinically approved drugs. This review discusses recently developed strategies to boost the antituberculous activity of ethionamide and antifolates. These approaches might help broaden the currently limited chemotherapeutic options of not only drug-resistant but also drug-susceptible tuberculosis, which still remains one of the most common infectious diseases in the developing world.

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Section: Antifolatesmentioning

confidence: 99%

Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

Wolff

Nguyen²

2012

Expert Review of Anti-infective Therapy

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“…(9) As can be seen, at the completion of the orientation step, the layout coordinates of molecules with different root fragments are approximately comparable, and the 2D coordinates now encode significant information about shared structural features.…”

Section: Methodsmentioning

confidence: 96%

2D Depiction of Fragment Hierarchies

Clark¹

2009

J. Chem. Inf. Model.

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Drug discovery projects often involve organizing compounds in the form of a hierarchical tree, where each node is a substructure fragment shared by all of its descendent nodes. A method is described for producing 2D depiction layout coordinates for each of the nodes in such a tree, ensuring that common fragments within molecular structures are drawn in an identical way, and arranged with a consistent orientation. This is achieved by first deriving a common numbering scheme for common fragments, then using this scheme to redepict each of the molecules, one fragment at a time, so that common fragments have common depiction motifs. Once complete, the distinct root branches can be overlaid onto each other, after which all of the fragments and whole molecules have a common layout and orientation. Several methods are described for preparing visual representations of molecular structure hierarchies alongside activity information. Combining high level tree display and structure depiction showing common features readily facilitates insight into structure−activity relationships.

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“…With the exception of a recent study, 10 efforts to increase potency have often led to a decrease in species-specificity. 11,12 The idea that a novel allosteric site important for catalysis may be targeted for species-specific inhibitor design is an attractive prospect. In a previous validation study, we utilized virtual screening to target a pocket near the crossover helix and were able to find micromolar-range inhibitors of Cryptosporidium hominis thymidylate synthase–dihydrofolate reductase, Ch TS–DHFR.…”

Section: Introductionmentioning

confidence: 99%

Exploring novel strategies for AIDS protozoal pathogens: α-helix mimetics targeting a key allosteric protein–protein interaction in C. hominis thymidylate synthase-dihydrofolate reductase (TS-DHFR)

et al. 2013

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The bifunctional enzyme thymidylate synthase–dihydrofolate reductase (TS–DHFR) from the protozoal parasite Cryptosporidium hominis is a potential molecular target for the design of antiparasitic therapies for AIDS-related opportunistic infections. The enzyme exists as a homodimer with each monomer containing a unique swap domain known as a “crossover helix” that binds in a cleft on the adjacent DHFR active site. This crossover helix is absent in species containing monofunctional forms of DHFR such as human. An in-depth understanding of protein–protein interactions between the crossover helix and adjacent DHFR active site that might modulate enzyme integrity or function would allow for insights into rational design of species-specific allosteric inhibitors. Mutational analysis coupled with structural studies and biophysical and kinetic characterization of crossover helix mutants identifies this domain as essential for full enzyme stability and catalytic activity, and pinpoints these effects to distinct faces of the crossover helix important in protein–protein interactions. Moreover, targeting this helical protein interaction with α-helix mimetics of the crossover helix leads to selective inhibition and destabilization of the C. hominis TS–DHFR enzyme, thus validating this region as a new avenue to explore for species-specific inhibitor design.

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Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of Cryptosporidium parvum Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations

Cited by 49 publications

References 76 publications

Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

2D Depiction of Fragment Hierarchies

Exploring novel strategies for AIDS protozoal pathogens: α-helix mimetics targeting a key allosteric protein–protein interaction in C. hominis thymidylate synthase-dihydrofolate reductase (TS-DHFR)

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