Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations

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 GpIbα 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.