Use of Molecular Dynamics for the Refinement of an Electrostatic Model for the In Silico Design of a Polymer Antidote for the Anticoagulant Fondaparinux

Molecular dynamics (MD) simulations results are herein incorporated into an electrostatic model used to determine the structure of an effective polymer-based antidote to the anticoagulant fondaparinux. In silico data for the polymer or its cationic binding groups has not, up to now, been available, and experimental data on the structure of the polymer-fondaparinux complex is extremely limited. Consequently, the task of optimizing the polymer structure is a daunting challenge. MD simulations provided a means to gain microscopic information on the interactions of the binding groups and fondaparinux that would have otherwise been inaccessible. This was used to refine the electrostatic model and improve the quantitative model predictions of binding affinity. Once refined, the model provided guidelines to improve electrostatic forces between candidate polymers and fondaparinux in order to increase association rate constants. 1. Introduction While anticoagulation therapy is widely used, it has certain undesirable side effects such as the potential to cause life-threatening hemorrhages. Such bleeding complications can be mitigated, in the event of an overdose of anticoagulants, by the administration of antidotes which neutralize the anticoagulants while still avoiding thrombosis [1, 2]. The most commonly used anticoagulants are heparin-derived drugs [3], which include unfractionated heparin (UFH), low molecular weight heparins (LMWHs), and the synthetic pentasaccharide derivatives fondaparinux and idraparinux [4–7]. Because of its predictable dose response, almost complete bioavailability [4, 7], increased half-life [1], and no occurrence of heparin-induced thrombocytopenia [5], fondaparinux is becoming increasingly important in clinical medicine; however, its widespread use is limited by a lack of a specific antidote. Administration of protamine, the antidote for UFH and LMWHs, does not reverse the anticoagulant effect of fondaparinux, and hemodialysis only reduces fondaparinux plasma levels by 20% [1]. Hence, the development of a clinically safe antidote for this anticoagulant has become critical [8]. Currently, only limited experimental work has been reported for the development of an antidote to fondaparinux. It has been shown that heparinase I and the recombinant factor VII (rVIIa) can partially reverse fondaparinux in vitro; however, these studies were limited in scope: there is no clinical data for heparinase I, and there is only one volunteer study and one clinical case for rVIIa [1]. More recently, Borgel et al. have experimentally developed