Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations.
Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations.
复制标题
通过对接和分子动力学模拟，探索在氧化条件下选择性靶向冯维勒布兰德因子的配体。
DOI：
10.1101/2024.03.22.586354
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Interlandi,Gianluca
中科院分区：
文献类型：
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作者：
Interlandi,Gianluca
血液蛋白von Willebrand因子(VWF)是一种大的多聚体蛋白，当被激活时，它与血小板结合，将它们拴在血管损伤的部位，并启动凝血。这一过程对正常的止血反应至关重要，但在炎症条件下，它被认为是病理性血栓形成的主要参与者。因此，VWF一直是抗血栓治疗药物发展的靶点。然而，在防止病理性血栓形成的同时仍然允许正常的生理性凝血是具有挑战性的，因为目前已知的抗血栓治疗药物会导致不必要的出血，特别是颅内出血。这项工作探索了在病理性血栓形成过程中存在的炎症条件下选择性抑制VWF的可能性。特别是，vwf的A2结构域被认为可以抑制邻近的A1结构域与血小板表面受体GPIBα的结合，这种自动抑制机制已被证明可以通过炎症过程中释放的氧化剂来消除。因此，找到仅在氧化条件下结合在A1和A2之间界面的药物分子可以恢复这种自我抑制机制。在这里，通过结合计算对接、分子动力学模拟和自由能微扰计算，从ZINC15数据库中鉴定出一种配体，它与A1A2界面结合，在氧化条件下相互作用更强。这些结果为发现在炎症条件下选择性地与蛋白质结合的药物分子提供了一个框架。
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 and initiating blood coagulation. This process is critical for the normal hemostatic 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 hemorrhage. 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 an 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 the presence of inflammatory conditions.