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2cf8
From Proteopedia
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==Overview== | ==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. | 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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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: serine protease inhibitor complex]] | [[Category: serine protease inhibitor complex]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:14:35 2007'' |
Revision as of 19:08, 12 November 2007
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THROMBIN-METHOXY
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
2CF8 is a Protein complex structure of sequences from Homo sapiens with NA, CA, ESH and SIN as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: AC1. 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 Mon Nov 12 21:14:35 2007
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. | CA | ESH | NA | SIN | Acute phase | Blood coagulation | Calcium-binding | Complex hydrolase/inhibitor | Glycoprotein | Hydolase | Serine protease | Serine protease inhibitor complex
