Research Papers

Journal of Computer-Aided Molecular Design

, Volume 10, Issue 1, pp 1-10

First online:

Functionality map analysis of the active site cleft of human thrombin

  • Peter D. J. GrootenhuisAffiliated withDepartment of Computational Medicinal Chemistry, N.V. Organon
  • , Martin KarplusAffiliated withDepartment of Chemistry, Harvard University

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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.


Thrombin inhibitors Molecular modelling Rational drug design MCSS method