Structure-Based Design of Selective Inhibitors of Dihydrofolate Reductase:  Synthesis and Antiparasitic Activity of 2,4-Diaminopteridine Analogues with a Bridged Diarylamine Side Chain

1999 ◽  
Vol 42 (23) ◽  
pp. 4853-4860 ◽  
Author(s):  
Andre Rosowsky ◽  
Vivian Cody ◽  
Nikolai Galitsky ◽  
Hongning Fu ◽  
Andrew T. Papoulis ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Side Chain ◽  
Selective Inhibitors ◽  
Antiparasitic Activity

The structure-based design and synthesis of selective inhibitors of trypanosoma cruzi dihydrofolate reductase

1999 ◽  
Vol 9 (10) ◽  
pp. 1463-1468 ◽  
Author(s):  
Fabio Zuccotto ◽  
Reto Brun ◽  
Dolores Gonzalez Pacanowska ◽  
Luis M. Ruiz Perez ◽  
Ian H. Gilbert
Keyword(s):  
Trypanosoma Cruzi ◽  
Dihydrofolate Reductase ◽  
Selective Inhibitors ◽  
Design And Synthesis

Targeting Kinetoplastid and Apicomplexan Thymidylate Biosynthesis as an Antiprotozoal Strategy

2019 ◽  
Vol 26 (22) ◽  
pp. 4262-4279 ◽  
Author(s):  
María Valente ◽  
Antonio E. Vidal ◽  
Dolores González-Pacanowska
Keyword(s):  
Dihydrofolate Reductase ◽  
Thymidylate Synthase ◽  
Nucleotide Metabolism ◽  
Human Pathogens ◽  
Antiparasitic Activity ◽  
Apicomplexan Parasites ◽  
Promising Area ◽  
Thymineless Death ◽  
Repair Pathways ◽  
Inhibitory Molecules

Kinetoplastid and apicomplexan parasites comprise a group of protozoans responsible for human diseases, with a serious impact on human health and the socioeconomic growth of developing countries. Chemotherapy is the main option to control these pathogenic organisms and nucleotide metabolism is considered a promising area for the provision of antimicrobial therapeutic targets. Impairment of thymidylate (dTMP) biosynthesis severely diminishes the viability of parasitic protozoa and the absence of enzymatic activities specifically involved in the formation of dTMP (e.g. dUTPase, thymidylate synthase, dihydrofolate reductase or thymidine kinase) results in decreased deoxythymidine triphosphate (dTTP) levels and the so-called thymineless death. In this process, the ratio of deoxyuridine triphosphate (dUTP) versus dTTP in the cellular nucleotide pool has a crucial role. A high dUTP/dTTP ratio leads to uracil misincorporation into DNA, the activation of DNA repair pathways, DNA fragmentation and eventually cell death. The essential character of dTMP synthesis has stimulated interest in the identification and development of drugs that specifically block the biochemical steps involved in thymine nucleotide formation. Here, we review the available literature in relation to drug discovery studies targeting thymidylate biosynthesis in kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp and Toxoplasma gondii) protozoans. The most relevant findings concerning novel inhibitory molecules with antiparasitic activity against these human pathogens are presented herein.

Molecular modeling toward selective inhibitors of dihydrofolate reductase from the biological warfare agent Bacillus anthracis

2015 ◽  
Vol 91 ◽  
pp. 63-71 ◽  
Author(s):  
Juliana O.S. Giacoppo ◽  
Daiana T. Mancini ◽  
Ana P. Guimarães ◽  
Arlan S. Gonçalves ◽  
Elaine F.F. da Cunha ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Bacillus Anthracis ◽  
Dihydrofolate Reductase ◽  
Biological Warfare ◽  
Selective Inhibitors ◽  
Biological Warfare Agent

scholarly journals Structure-Based Approach to the Development of Potent and Selective Inhibitors of Dihydrofolate Reductase fromCryptosporidium

2008 ◽  
Vol 51 (21) ◽  
pp. 6839-6852 ◽  
Author(s):  
David B. Bolstad ◽  
Erin S. D. Bolstad ◽  
Kathleen M. Frey ◽  
Dennis L. Wright ◽  
Amy C. Anderson
Keyword(s):  
Dihydrofolate Reductase ◽  
Selective Inhibitors

scholarly journals Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl Fluorides

2018 ◽  
Vol 61 (12) ◽  
pp. 5395-5411 ◽  
Author(s):  
Raik Artschwager ◽  
David J. Ward ◽  
Susan Gannon ◽  
Arwin J. Brouwer ◽  
Helmus van de Langemheen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Side Chain ◽  
Selective Inhibitors

scholarly journals Crystal Structure of Bacillus anthracis Dihydrofolate Reductase with the Dihydrophthalazine-Based Trimethoprim Derivative RAB1 Provides a Structural Explanation of Potency and Selectivity

2009 ◽  
Vol 53 (7) ◽  
pp. 3065-3073 ◽  
Author(s):  
Christina R. Bourne ◽  
Richard A. Bunce ◽  
Philip C. Bourne ◽  
K. Darrell Berlin ◽  
Esther W. Barrow ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Dihydrofolate Reductase ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Side Chain ◽  
Natural Substrate ◽  
X Ray Diffraction ◽  
Structural Explanation ◽  
X Ray ◽  
Hydrophobic Anchor

ABSTRACT Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (≤12.8 μg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P212121, and X-ray diffraction data were collected to a 2.3-Å resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.

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