5AF9: Thrombin in complex with 4-Methoxy-N-(2-pyridinyl)benzamide

Citation:
Abstract
In lead optimization, small, enthalpically advantaged fragments have been suggested to be superior, as an entropic component will be added inevitably during late-stage optimization. Determination of thermodynamic signatures of weak-binding fragments is essential to support the decision-making process, to decide which fragment to take to further optimization. High-resolution crystal structures of six fragments binding to the S1 pocket of thrombin were determined and analyzed with respect to their thermodynamic profile. The two most potent fragments exhibiting an amidine-type scaffold are not the most enthalpic binders; instead a chloro-thiophene fragment binds more enthalpically. Two chemically very similar chloro-aromatic fragments differ strongly in their potency (430 muM vs 10 mM); their binding modes are related, but the surrounding residual water network differs. The more potent one recruits a water molecule and involves Glu192 in binding, thus succeeding in firmly capping the S1 pocket. Fragments exhibiting a rather perfect solvation pattern in their binding mode also experience the highest potency.
PDB ID: 5AF9Download
MMDB ID: 132095
PDB Deposition Date: 2015/1/20
Updated in MMDB: 2015/09
Experimental Method:
x-ray diffraction
Resolution: 1.18  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 5AF9: trimeric; determined by author and by software (PISA)
Molecular Components in 5AF9
Label Count Molecule
Proteins (3 molecules)
1
Thrombin Heavy Chain(Gene symbol: F2)
Molecule annotation
1
Hirudin Variant-2
Molecule annotation
1
Thrombin Light Chain(Gene symbol: F2)
Molecule annotation
Chemicals (11 molecules)
1
1
2
2
3
2
4
1
5
1
6
3
7
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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