In Silico Design of Polymeric Antidote for Anticoagulant Fondaparinux

The use of unfractionated heparin (UFH) and heparin derivatives as anticoagulants is an essential clinical practice in modern medicine. An overdose of these medications can lead to life-threatening bleeding episodes, and therefore antidotes arc required. Fondaparinux is a new heparin derivative that has heroine increasingly important in clinical medicine due to its advantages over current anticoagulants. However, there is no antidote currently available for fondaparinux, and its utilization in clinics can be significantly increased by developing an effective antidote. In this article, we report the development of a mathematical model to aid the design of a polymer-based antidote for fondaparinux. A model was developed to characterize the binding between the polymer and fondaparinux. This model allows for the rapid testing of testing polymer candidate structures in silico and thus reduces both the cost and time associated with the trial and error approach to polymer development. The model calculates the association rate constant (k(subscript a)) from a modified Debye-Huckel equation for electrostatic interactions between charged molecules and uses this as a metric for binding affinity. The polymer is modeled as a sphere with cationic binding units randomly placed on its surface. Its size and the number and flexibility of binding units were studied through computer simulations. This model indicated that the binding units were flexible in nature and were spaced at least 9.85×10^(-10) m apart on the polymer surface. Furthermore, it was found that smaller polymers exhibit higher k(subscript a), values and a greater binding unit efficiency, indicating that reducing the size of the polymer molecules would enhance binding. Given the very limited information available on the interactions between the polymer and fondaparinux, this mathematical model is a powerful tool to provide qualitative information on these interactions and their electrostatic rate enhancement.

[1]  Robert J. Linhardt,et al.  Heparin—Protein Interactions , 2002 .

[2]  S Alban,et al.  From heparins to factor Xa inhibitors and beyond , 2005, European journal of clinical investigation.

[3]  S. Schulman,et al.  Anticoagulants and their reversal. , 2007, Transfusion medicine reviews.

[4]  J. Th. G. Overbeek,et al.  The electrical Duoble Layer and the Theory of Electrophoresis , 1978 .

[5]  J. Ferguson,et al.  Low-Molecular-Weight Heparins , 2008, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[6]  Souvik Maiti,et al.  Blood compatibility of novel water soluble hyperbranched polyglycerol-based multivalent cationic polymers and their interaction with DNA. , 2006, Biomaterials.

[7]  Elaine Gray,et al.  Heparin and low-molecular-weight heparin , 2008, Thrombosis and Haemostasis.

[8]  Brian K Adler,et al.  Unfractionated Heparin and Other Antithrombin Mediated Anticoagulants , 2004, American Society for Clinical Laboratory Science.

[9]  J. Weitz,et al.  Emerging anticoagulants for the treatment of venous thromboembolism , 2006, Thrombosis and Haemostasis.

[10]  J. Weitz.  Low-molecular-weight heparins. , 1997, The New England journal of medicine.

[11]  J. Weitz,et al.  New anticoagulants , 2005, Journal of thrombosis and haemostasis : JTH.

[12]  Gideon Schreiber,et al.  New insights into the mechanism of protein–protein association , 2001, Proteins.

[13]  M. D. Freedman,et al.  Pharmacodynamics, Clinical Indications, and Adverse Effects of Heparin , 1992, Journal of clinical pharmacology.

[14]  J. Aqvist,et al.  A new method for predicting binding affinity in computer-aided drug design. , 1994, Protein engineering.

[15]  Roderick E. Hubbard,et al.  3D structure and the drug-discovery process , 2005 .

[16]  J Ingerslev,et al.  Use of recombinant factor VIIa for emergency reversal of anticoagulation. , 2007, Journal of postgraduate medicine.

[17]  Yaroslav Filinchuk,et al.  A flexible tripodal ligand linking octametallic terbium rings into luminescent polymeric chains. , 2008, Chemical communications.

[18]  G Schreiber,et al.  Predicting the rate enhancement of protein complex formation from the electrostatic energy of interaction. , 1999, Journal of molecular biology.

[19]  P. V. von Hippel,et al.  Diffusion-controlled macromolecular interactions. , 1985, Annual review of biophysics and biophysical chemistry.

[20]  Patrick F. Fogarty,et al.  Diagnosis and management of venous thromboembolism. , 2008, The Medical clinics of North America.

[21]  M Sobel,et al.  Structure-function relations of antithrombin III-heparin interactions as assessed by biophysical and biological assays and molecular modeling of peptide-pentasaccharide-docked complexes. , 1996, Archives of biochemistry and biophysics.

[22]  J. Weitz,et al.  Beyond heparin and warfarin: the new generation of anticoagulants , 2007, Expert opinion on investigational drugs.

[23]  Gideon Schreiber,et al.  Fundamental Aspects of Protein—Protein Association Kinetics , 2009 .

[24]  Gideon Schreiber,et al.  Rational design of faster associating and tighter binding protein complexes , 2000, Nature Structural Biology.

[25]  Jeffrey I. Weitz,et al.  Emerging Anticoagulant Drugs , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[26]  Kenichi A Tanaka,et al.  The anticoagulated patient: strategies for effective blood loss management. , 2007, Surgery.