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PDBsum entry 3da9
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References listed in PDB file
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Key reference
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Title
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Compounds binding to the s2-S3 pockets of thrombin.
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Authors
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M.Nilsson,
M.Hämäläinen,
M.Ivarsson,
J.Gottfries,
Y.Xue,
S.Hansson,
R.Isaksson,
T.Fex.
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Ref.
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J Med Chem, 2009,
52,
2708-2715.
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PubMed id
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Abstract
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A set of compounds designed to bind to the S2-S3 pockets of thrombin was
prepared. These compounds included examples with no interactions in the S1
pocket. Proline, a common P2 in many thrombin inhibitors, was combined with
known P3 residues and P1 substituents of varying size and lipophilicity. Binding
constants were determined using surface plasmon resonance (SPR) biosensor
technology and were found to be in good agreement with results from an enzyme
assay. A dramatic increase in affinity (100-1000 times) was seen for compounds
incorporating an amino group capable of forming a hydrogen bond with gly216 in
the protein backbone. The ligand efficiency was increased by including
substituents that form stronger hydrophobic interactions with the P1 pocket. The
binding mode was confirmed by X-ray analysis, which revealed the anticipated
binding motif that included hydrogen bonds as well as a tightly bound water
molecule. A QSAR model indicated that hydrogen bonding and lipophilicity were
important for the prediction of binding constants. The results described here
may have implications for how directed compound libraries for shallow protein
pockets, like S2 and S3 in serine proteases, can be designed.
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