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

  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},
  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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These studies underscore the efficiency of combining structure-based drug design with combinatorial chemistry to produce effective species-specific enzyme inhibitors of medicinal importance.
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Rationally targeting an essential enzyme in a parasitic organism has yielded specific enzyme inhibitors capable of suppressing that parasite's growth.
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Crystal structures of Giardia lamblia guanine phosphoribosyltransferase at 1.75 A(,).
The G. lamblia GPRTase exhibits substantial structural differences from known purine phosphoribosyltransferases at positions remote from the catalytic site, but conserves most contacts to the bound inhibitor.
The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor.
The X-ray crystal structures and NMR spectra reveal chemical and structural features that suggest a strategy for the design of malaria-specific transition-state inhibitors and differences in hydrogen bonding between the transition- state analogue complexes of the human and malarial HG(X)PRTases.
Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase.
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These studies underscore the feasibility of using structure-based drug design to transform a mediocre lead compound into a potent enzyme inhibitor and suggest that energy production can be blocked in trypanosomatids with a tight binding competitive inhibitor of an enzyme in the glycolytic pathway.
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Computer model-built structures are used to identify computationally and to confirm experimentally the activity of nonpeptidic inhibitors directed against important enzymes in the schistosome and malaria parasite life cycles.