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Related Experiment Videos

Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode.

A von Matt1, C Ehrhardt, P Burkhard

  • 1Novartis Pharma AG, Basel, Switzerland. anette.von_matt@pharma.novartis.com

Bioorganic & Medicinal Chemistry
|October 12, 2000
PubMed
Summary

Novel thrombin inhibitors were developed using amino boronic acids. Unexpectedly, compounds with bulky side chains, too large for the S1 pocket, showed potent nanomolar inhibition, revealing a new binding mode.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Structural Biology

Background:

  • Thrombin is a key enzyme in blood coagulation.
  • Inhibitors targeting thrombin are crucial for anticoagulant therapies.
  • Understanding enzyme-inhibitor interactions guides drug design.

Purpose of the Study:

  • To synthesize and evaluate novel thrombin inhibitors based on structural insights of the S1 pocket.
  • To investigate the inhibitory activity of derivatives with varying side-chain sizes.
  • To elucidate the binding mechanism of potent inhibitors.

Main Methods:

  • Synthesis of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives.
  • Structural comparison of the S1 pocket in trypsin-like serine proteases.

Related Experiment Videos

  • Enzyme inhibition assays to determine potency (nM range).
  • X-ray crystallography to determine the inhibitor-thrombin complex structure.

    • Main Results:

    • A series of novel thrombin inhibitors were synthesized.
    • Compounds with side chains too large for the S1 pocket exhibited potent nanomolar inhibition.
    • X-ray structure revealed a previously unrecognized binding mode for these inhibitors.

    Conclusions:

    • The study identified potent thrombin inhibitors with an unexpected binding mode.
    • Structural flexibility or alternative interactions allow inhibition despite S1 pocket steric hindrance.
    • These findings offer new strategies for designing effective anticoagulants.