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Predicting binding affinities of a novel polymer for the neutralization of fondaparinux

University of British Columbia

Anticoagulants are an essential clinical tool in modern medicine where they are administered to patients who are undergoing procedures such as cardiac surgery and kidney dialysis. They are also used to treat serious illnesses including venous thromboembolism, unstable angina, and acute myocardial infarction. However, anticoagulants have undesirable side effects, most notably excessive bleeding. Thus, antidotes are required to rapidly reverse the anticoagulant effect and treat life-threatening bleeding complications that might arise from an overdose of anticoagulants or the urgent need to perform an invasive procedure. For instance, while the synthetic anticoagulant fondaparinux has become increasingly important in clinical medicine because of its advantages over other heparin-based drugs, its use is limited by a lack of an antidote. The development of an effective, clinically safe antidote for fondaparinux is therefore critical for its widespread adoption in clinical medicine. The synthetic polymer HBSPCM (Heparin Binding Synthetic Polyvalent Cationic Macromolecule) has been found to be a promising candidate antidote for fondaparinux. However, an optimal design of HBSPCM that binds to fondaparinux with high affinity and neutralizes it has not yet been determined. A robust model is herein developed that describes the electrostatic interactions between fondaparinux and candidate HBSPCMs using data gathered from experimental work as well as molecular dynamics (MD) simulations. This model is then used to characterize the binding affinities of various putative HBSPCM structures for fondaparinux. This enables the prediction of an improved structure for the initial design of an antidote molecule. The synthesis and testing of every possible candidate HBSPCM structure would be costly and time-consuming. By quickly and efficiently predicting molecular structures that show promising binding affinities to fondaparinux, the mathematical model described in this thesis is a vast improvement over a traditional trial-and-error approach to drug design. As such, it represents an essential theoretical tool in the development of fondaparinux as an effective and safe anticoagulation treatment.

Text

2013-01-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43760

Biomedical Engineering

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/