Exploring ligands that target von Willebrand factor selectively under
oxidizing conditions through docking and molecular dynamics simulations
Abstract
The blood protein von Willebrand factor (VWF) is a large multimeric
protein that, when activated, binds to blood platelets tethering them to
the site of vascular injury initiating blood coagulation. This process
is critical for the normal haemostatic response, but especially under
inflammatory conditions it is thought to be a major player in
pathological thrombus formation. For this reason, VWF has been the
target for the development of anti-thrombotic therapeutics. However, it
is challenging to prevent pathological thrombus formation while still
allowing normal physiological blood coagulation as currently available
anti-thrombotic therapeutics are known to cause unwanted bleeding in
particular intracranial haemorrhage. This work explores the possibility
of inhibiting VWF selectively under the inflammatory conditions present
during pathological thrombus formation. In particular, the A2 domain of
VWF is known to inhibit the neighboring A1 domain from binding to the
platelet surface receptor GpIb α and this auto-inhibitory
mechanism has been shown to be removed by oxidizing agents released
during inflammation. Hence, finding drug molecules that bind at the
interface between A1 and A2 only under oxidizing conditions could
restore such auto-inhibitory mechanism. Here, by using a combination of
computational docking, molecular dynamics simulations and free energy
perturbation calculations, a ligand from the ZINC15 database was
identified that binds at the A1A2 interface with the interaction being
stronger under oxidizing conditions. The results provide a framework for
the discovery of drug molecules that bind to a protein selectively in
inflammatory conditions.