2cf8: Difference between revisions

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.

2CF8 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NA, CA, ESH and SIN as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CF8 OCA].  

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