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PDBsum entry 2cf8
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Hydrolase/hydrolase inhibitor
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PDB id
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2cf8
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References listed in PDB file
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Key reference
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Title
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Multipolar interactions in the d pocket of thrombin: large differences between tricyclic imide and lactam inhibitors.
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Authors
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E.Schweizer,
A.Hoffmann-Röder,
J.A.Olsen,
P.Seiler,
U.Obst-Sander,
B.Wagner,
M.Kansy,
D.W.Banner,
F.Diederich.
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Ref.
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Org Biomol Chem, 2006,
4,
2364-2375.
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PubMed id
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Abstract
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Two series of tricyclic inhibitors of the serine protease thrombin, imides
(+/-)-1-(+/-)-8 and lactams (+/-)-9-(+/-)-13, were analysed to evaluate
contributions of orthogonal multipolar interactions with the backbone C=O moiety
of Asn98 to the free enthalpy of protein-ligand complexation. The lactam
derivatives are much more potent and more selective inhibitors (K(i) values
between 0.065 and 0.005 microM, selectivity for thrombin over trypsin between
361- and 1609-fold) than the imide compounds (Ki values between 0.057 and 23.7
microM, selectivity for thrombin over trypsin between 3- and 67-fold). The
increase in potency and selectivity is explained by the favorable occupancy of
the P-pocket of thrombin by the additional isopropyl substituent in the lactam
derivatives. The nature of the substituent on the benzyl ring filling the D
pocket strongly influences binding potency in the imide series, with Ki values
increasing in the sequence: F < OCH2O < Cl < H < OMe < OH <
N(pyr)<< Br. This sequence can be explained by both steric fit and the
occurrence of orthogonal multipolar interactions with the backbone C[double
bond, length as m-dash]O moiety of Asn98. In contrast, the substituent on the
benzyl ring hardly affects the ligand potency in the lactam series. This
discrepancy was clarified by the comparison of X-ray structures solved for
co-crystals of thrombin with imide and lactam ligands. Whereas the benzyl
substituents in the imide inhibitors are sufficiently close (< or =3.5
Angstroms) to the C=O group of Asn98 to allow for attractive orthogonal
multipolar interactions, the distances in the lactam series are too large (>
or =4 Angstroms) for attractive dipolar contacts to be effective.
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