In Silico Design of Polymeric Antidote for Anticoagulant Fondaparinux

Adriana Cajiao ； Bhushan Gopaluni ； Ezra Kwok ； Jayachandran N. Kizhakkedathu

《Journal of Medical and Biological Engineering》 31卷2期 (2011/04) Pp. 129-134

並列摘要

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-Hückel 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.

並列關鍵字

Association rate constant ； Computer simulations ； Electrostatic interactions ； Fondaparinux ； Antidote ； Polymer