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Predicting pharmacologic efficacy of anticoagulants
Author(s) -
Orfeo Thomas,
Butenas Saulius,
BrummelZiedins Kathleen E,
Mann Kenneth G
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a631-d
Subject(s) - coagulation , anticoagulant , computational biology , heparin , discovery and development of direct thrombin inhibitors , anticoagulant drug , medicine , pharmacology , thrombin , chemistry , bioinformatics , biology , surgery , immunology , platelet
Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders and surgical intervention. Many new compounds that were plausible in terms of target, relative specificity, mechanism and kinetic and thermodynamic properties have failed to perform as expected when assessed, at significant expense, in vivo . Our current deterministic mathematical model (Hockin et al . J. Biol. Chem . 2002, 277 : ) describes the dynamic biochemical repair process that emerges in response to vascular injury and allows us to incorporate hypothetical inhibitors/enhancers at their proposed sites of interaction, thus providing an assessment of their efficacy. In conjunction with our coagulation proteome model (a synthetic reconstruction using purified protein of the components described in the computational model), we evaluated a set of anticoagulants currently in clinical use (unfractionated heparin, synthetic low molecular weight heparins, factor Xa inhibitors and thrombin inhibitors). The interactions of each anticoagulant with its target(s) were mathematically incorporated into the overall mathematical description of the reaction pathways. Outcomes for each anticoagulant at clinically relevant concentrations were generated and validated by comparisons with the synthetic coagulation proteome. Our results show that this type of mathematical methodology can lead to insights into drug performance and to rationalizing the differing properties that an ideal anticoagulant would require in therapeutic vs. prophylactic settings. Supported by NIH HL46703 (KGM)