2cf9
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Two series of tricyclic inhibitors of the serine protease thrombin, imides | + | 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. |
==Disease== | ==Disease== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Thrombin]] | [[Category: Thrombin]] | ||
| - | [[Category: Banner, D | + | [[Category: Banner, D W.]] |
[[Category: Diederich, F.]] | [[Category: Diederich, F.]] | ||
[[Category: Hoffmann-Roeder, A.]] | [[Category: Hoffmann-Roeder, A.]] | ||
[[Category: Kansy, M.]] | [[Category: Kansy, M.]] | ||
[[Category: Obst-Sander, U.]] | [[Category: Obst-Sander, U.]] | ||
| - | [[Category: Olsen, J | + | [[Category: Olsen, J A.]] |
[[Category: Schweizer, E.]] | [[Category: Schweizer, E.]] | ||
[[Category: Wagner, B.]] | [[Category: Wagner, B.]] | ||
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[[Category: serine protease inhibitor complex]] | [[Category: serine protease inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:48:00 2008'' |
Revision as of 14:48, 21 February 2008
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THROMBIN-METHOXY2
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
2CF9 is a Protein complex structure of sequences from Homo sapiens with , , and as ligands. Active as Thrombin, with EC number 3.4.21.5 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors., Schweizer E, Hoffmann-Roder A, Olsen JA, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, Org Biomol Chem. 2006 Jun 21;4(12):2364-75. Epub 2006 May 10. PMID:16763681
Page seeded by OCA on Thu Feb 21 16:48:00 2008
Categories: Homo sapiens | Protein complex | Thrombin | Banner, D W. | Diederich, F. | Hoffmann-Roeder, A. | Kansy, M. | Obst-Sander, U. | Olsen, J A. | Schweizer, E. | Wagner, B. | 348 | CA | NA | SIN | Acute phase | Blood coagulation | Calcium-binding | Complex hydrolase/inhibitor | Glycoprotein | Hydolase | Serine protease | Serine protease inhibitor complex
