Design of Polyphosphate Inhibitors: A Molecular Dynamics Investigation on Polyethylene Glycol-Linked Cationic Binding Groups

Abstract

Inorganic polyphosphate (polyP) released by human platelets has recently been shown to activate blood clotting and identified as a potential target for the development of novel antithrombotics. Recent studies have shown that polymers with cationic binding groups (CBGs) inhibit polyP and attenuate thrombosis. However, a good molecular-level understanding of the binding mechanism is lacking for further drug development. While molecular dynamics (MD) simulation can provide molecule-level information, the time scale required to simulate these large biomacromolecules makes classical MD simulation impractical. To overcome this challenge, we employed metadynamics simulations with both all-atom and coarse-grained force fields. The force field parameters for polyethylene glycol (PEG) conjugated CBGs and polyP were developed to carry out coarse-grained MD simulations, which enabled simulations of these large biomacromolecules in a reasonable time scale. We found that the length of the PEG tail does not impact the interaction between the (PEG) -CBG and polyP. As expected, increasing the number of the charged tertiary amine groups in the head group strengthens its binding to polyP. Our simulation shows that (PEG) -CBG initially form aggregates, mostly with the PEG in the core and the hydrophilic CBG groups pointing toward water; then the aggregates approach the polyP and sandwich the polyP to form a complex. We found that the binding of (PEG)-CBG remains intact against various lengths of polyP. Binding thermodynamics for two of the (PEG) -CBG/polyP systems simulated were measured by isothermal titration calorimetry to confirm the key finding of the simulations that the length PEG tail does not influence ligand binding to polyP.

Wechselwirkung von Polyelektrolyt‐Architekturen mit Proteinen und Biosystemen

“…Zur Überwindung dieser Nachteile entwickelte die Kizhakkedathu‐Gruppe vor kurzem eine UHRA, ein synthetisches, nicht toxisches makromolekulares Heparin‐Gegenmittel, das in der Lage ist, alle klinisch verfügbaren Antikoagulanzien auf Heparinbasis zu neutralisieren [41, 43, 239–242] . Abbildung 13 a zeigt die chemische Struktur der UHRA und ihre Art der Interaktion mit dem Antithrombin/Heparin‐Komplex (Abbildung 13 b).…”

“…Auch die Interaktion von dPGS mit Nervenzellen war bereits Gegenstand mehrerer Studien [39, 40] . Positiv geladene substituierte Polyglycerine wurden als stark blutungshemmende Mittel identifiziert, welche die gerinnungshemmende Wirkung von Heparin umkehren können [41–43] …”

“…Organe stellen den höchsten Komplexitätsgrad dar, und das Verständnis ihrer Wechselwirkung mit synthetischen Polyelektrolytsystemen steht noch am Anfang. Seit kurzem werden jedoch kationische Polyelektrolyte mit geeigneter Architektur als Wirkstoffe eingesetzt, die die gerinnungshemmende Wirkung von Antikoagulantien im Blut umkehren [41–43] . Die Matrix in Abbildung 2 gibt einen guten Überblick über mögliche medizinische Herausforderungen, für die synthetische Polyelektrolyte Lösungen bieten können.…”

Understanding the Interaction of Polyelectrolyte Architectures with Proteins and Biosystems

“…Furthermore, its interaction with neural microglia has been the subject of several studies [39, 40] . Substituted polyglycerols bearing positive charges have been introduced as potent antibleeding agents with excellent anticoagulant reversal activity upon binding the polyanion heparin [41–43] …”

“…Organs present the highest level of complexity and the understanding of their interaction with synthetic polyelectrolyte systems is in its infancy. However, cationic polyelectrolytes with suitable architectures have recently been introduced as agents with anticoagulant reversal activity in blood [41–43] . The entire matrix of systems and problems gives a good overview of the possible medical problems to which synthetic polyelectrolytes may provide solutions.…”