Department of Physics, Pukyong National University, Busan 48513, Republic of Korea.
R&D Center, PharmCADD Co., Ltd., Busan 48792, Republic of Korea.
Molecules. 2023 Oct 2;28(19):6909. doi: 10.3390/molecules28196909.
Thromboembolic disorders, arising from abnormal coagulation, pose a significant risk to human life in the modern world. The FDA has recently approved several anticoagulant drugs targeting factor Xa (FXa) to manage these disorders. However, these drugs have potential side effects, leading to bleeding complications in patients. To mitigate these risks, coagulation factor IXa (FIXa) has emerged as a promising target due to its selective regulation of the intrinsic pathway. Due to the high structural and functional similarities of these coagulation factors and their inhibitor binding modes, designing a selective inhibitor specifically targeting FIXa remains a challenging task. The dynamic behavior of protein-ligand interactions and their impact on selectivity were analyzed using molecular dynamics simulation, considering the availability of potent and selective compounds for both coagulation factors and the co-crystal structures of protein-ligand complexes. Throughout the simulations, we examined ligand movements in the binding site, as well as the contact frequencies and interaction fingerprints, to gain insights into selectivity. Interaction fingerprint (IFP) analysis clearly highlights the crucial role of strong H-bond formation between the ligand and D189 and A190 in the S1 subsite for FIXa selectivity, consistent with our previous study. This dynamic analysis also reveals additional FIXa-specific interactions. Additionally, the absence of polar interactions contributes to the selectivity for FXa, as observed from the dynamic profile of interactions. A contact frequency analysis of the protein-ligand complexes provides further confirmation of the selectivity criteria for FIXa and FXa, as well as criteria for binding and activity. Moreover, a ligand movement analysis reveals key interaction dynamics that highlight the tighter binding of selective ligands to the proteins compared to non-selective and inactive ligands.
血栓栓塞性疾病源于异常凝血，在现代社会对人类生命构成重大威胁。美国食品药品监督管理局（FDA）最近批准了几种靶向因子 Xa（FXa）的抗凝药物来治疗这些疾病。然而，这些药物有潜在的副作用，会导致患者出血并发症。为了降低这些风险，凝血因子 IXa（FIXa）因其对内在途径的选择性调节而成为一个有前途的靶点。由于这些凝血因子及其抑制剂结合模式具有高度的结构和功能相似性，设计一种针对 FIXa 的选择性抑制剂仍然是一项具有挑战性的任务。利用分子动力学模拟分析了蛋白质-配体相互作用的动态行为及其对选择性的影响，同时考虑了针对这两种凝血因子的有效且选择性化合物以及蛋白质-配体复合物的共晶结构的可用性。在整个模拟过程中，我们研究了配体在结合部位的运动情况，以及接触频率和相互作用指纹，以深入了解选择性。相互作用指纹（IFP）分析清楚地强调了配体与 D189 和 A190 在 S1 亚位点形成强氢键对于 FIXa 选择性的关键作用，这与我们之前的研究一致。这种动态分析还揭示了其他 FIXa 特异性相互作用。此外，由于相互作用的动态特征，缺乏极性相互作用有助于 FXa 的选择性。对蛋白质-配体复合物的接触频率分析进一步证实了 FIXa 和 FXa 的选择性标准，以及结合和活性标准。此外，配体运动分析揭示了关键的相互作用动态，突出了选择性配体与蛋白质的紧密结合，与非选择性和非活性配体相比。
