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PDBsum entry 1ypm
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Blood clotting/hydrolase inhibitor
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PDB id
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1ypm
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References listed in PDB file
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Key reference
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Title
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Design and X-Ray crystal structures of human thrombin with synthetic cyanopeptide-Analogues.
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Authors
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G.Radau,
J.Fokkens.
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Ref.
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Pharmazie, 2007,
62,
83-88.
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PubMed id
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Abstract
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Based on the X-ray crystals of cocrystallized cyanopeptide-trypsin and
cyanopeptide-thrombin-com-plexes, a rational drug design succeeded in the
establishment of suitable lead structures for the development of new potential
inhibitors of thrombin. This report deals with the design and X-ray
crystallography data of new synthetic, low-molecular weight
cyanopeptide-analogues, RA-1008 and RA-1014, complexed with human alpha-thrombin
at 1.85 A resolution. The crystal structures of the complexes reveal, by analogy
with modeling studies, that the salt bridge of Asp189 to this type of synthetic
thrombin inhibitors leads to an almost identically binding into the S1
specificity pocket in comparison to the complex of the natural products, whereas
in the overall binding modes the P2-P4 substructures differ from those of the
leads. The strongest member of the second series of described thrombin
inhibitors, RA-1014, shows in the crystal complex with thrombin a slightly
higher affinity towards the enzyme than RA-1008 as confirmed by inhibition
tests. This result and other key informations will be helpful to design a more
potent series of inhibitors.
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