Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase

@article{Aronov2001VirtualSO,
  title={Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase},
  author={Alex M. Aronov and Narsimha R. Munagala and Irwin D. Kuntz and Ching C. Wang},
  journal={Antimicrobial Agents and Chemotherapy},
  year={2001},
  volume={45},
  pages={2571 - 2576}
}
ABSTRACT Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional… 
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GPRT plays an essential role in supplying guanine nucleotides required for growth and multiplication of Giardia, emphasizing its potential as a bona fide target for antigiardiasis chemotherapy.
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It is discovered that the nontoxic nucleoside analogue 2-fluoro-2′-deoxyadenosine (F-dAdo) is a “subversive substrate” for T. vaginalis PNP, and the structures of the TvPNP complexes suggest opportunities for further improved subversive substrates beyond F- dAdo.
The Adenine Phosphoribosyltransferase from Giardia lamblia Has a Unique Reaction Mechanism and Unusual Substrate Binding Properties*
TLDR
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The acyclic nucleoside phosphonates (ANPs) appear to be excellent candidates because they are good inhibitors of the two Plasmodium enzymes, can be selective compared to the human enzyme, can arrest parasitemia in cell based assays, have low cytotoxicity to thehuman host cell and, because of their stable carbon-phosphorous bond, are stable within the cell.
Phosphoribosyltransferase mechanisms and roles in nucleic acid metabolism.
Adenosine is the primary precursor of all purine nucleotides in Trichomonas vaginalis.
Crystal structures of APRT from Francisella tularensis – an N–H···N hydrogen bond imparts adenine specificity in adenine phosporibosyltransferases
TLDR
Analysis of the structures of apo and adenine‐bound APRT from F. tularensis suggests that the base‐binding loop not only confers appropriate affinity but also provides defined specificity foradenine, and proposes the mechanism by which these evolutionarily divergent enzymes achieve base specificity.
Identification of Similar Binding Sites to Detect Distant Polypharmacology
TLDR
Structural-based methods aiming at identifying similar binding sites may offer an alternative complementary means to ligand‐based methods for detecting distant polypharmacology.
A guide to drug discovery: Designing screens: how to make your hits a hit
TLDR
A recent trend in high-throughput screening has been to place less emphasis on the number of data points that can be produced, and to focus instead on the quality of the data obtained.
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