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Journal of Computer-Aided Molecular Design

, Volume 14, Issue 6, pp 507–529 | Cite as

Factor Xa: Simulation studies with an eye to inhibitor design

  • Xavier Daura
  • Eric Haaksma
  • Wilfred F. van Gunsteren
Article

Abstract

Factor Xa is a serine protease which activates thrombin and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is at the crossroads of the extrinsic and intrinsic pathways of coagulation and, hence, has become an important target for the design of anti-thrombotics (inhibitors). It is not known to be involved in other processes than hemostasis and its binding site is different to that of other serine proteases, thus facilitating selective inhibition. The design of high-affinity selective inhibitors of factor Xa requires knowledge of the structural and dynamical characteristics of its active site. The three-dimensional structure of factor Xa was resolved by X-ray crystallography and refined at 2.2 Å resolution by Padmanabhan and collaborators. In this article we present results from molecular dynamics simulations of the catalytic domain of factor Xa in aqueous solution. The simulations were performed to characterise the mobility and flexibility of the residues delimiting the unoccupied binding site of the enzyme, and to determine hydrogen bonding propensities (with protein and with solvent atoms) of those residues in the active site that could interact with a substrate or a potential inhibitor. The simulation data is aimed at facilitating the design of high-affinity selective inhibitors of factor Xa.

biomolecular simulation drug design factor Xa GROMOS molecular dynamics 

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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Xavier Daura
    • 1
  • Eric Haaksma
    • 2
  • Wilfred F. van Gunsteren
    • 1
  1. 1.Laboratory of Physical ChemistrySwiss Federal Institute of Technology Zürich, ETH ZentrumZürichSwitzerland
  2. 2.Department of Chemical ResearchBoehringer Ingelheim Pharma KGBiberach an der RissGermany

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