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Functionality map analysis of the active site cleft of human thrombin

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Summary

The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensional surface of a protein. The positions of 10 functional group sites are compared with those of corresponding groups of four thrombin-inhibitor complexes. Many, but not all features, of known thrombin inhibitors are reproduced by the method. The results indicate that certain aspects of the binding modes of these inhibitors are not optimal. In addition, suggestions are made for improving binding by interaction with functional group sites on the thrombin surface that are not used by the thrombin inhibitors.

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Authors and Affiliations

  1. Department of Computational Medicinal Chemistry, N.V. Organon, P.O. Box 20, 5340 BH, Oss, The Netherlands

    Peter D. J. Grootenhuis

  2. Department of Chemistry, Harvard University, 12 Oxford Street, 02138, Cambridge, MA, U.S.A.

    Martin Karplus

Authors
  1. Peter D. J. Grootenhuis
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  2. Martin Karplus
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Additional information

Abbreviations: MCSS, multiple copy simultaneous search; PPACK, d-phenylalanyl-l-propyl-l-arginine chloromethane; NAPAP, N α-(2-naphthylsulfonylglycyl)-d-para-amidinophenylalanylpiperidine; argatroban, (2R,4R)-4-methyl-1-[N α-(3-methyl-1,2,3,4-tetrahydro-8-quinolinylsulfonyl)-l-arginyl]-2-piperidine carboxylic acid; rms, root mean square. The thrombin residues are numbered according to the chymotrypsin-based numbering by Bode et al. [8]. P1, P2, P3, etc., denote the peptide inhibitor residues on the amino-terminal side of the scissile peptide bond, and S1, S2, S3, etc., the corresponding subsites of thrombin

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Grootenhuis, P.D.J., Karplus, M. Functionality map analysis of the active site cleft of human thrombin. J Computer-Aided Mol Des 10, 1–10 (1996). https://doi.org/10.1007/BF00124460

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