Department of Physics, Pukyong National University, Busan 48513, Korea.
R&D Center of PharmCADD, Busan 48060, Korea.
Molecules. 2021 Sep 3;26(17):5372. doi: 10.3390/molecules26175372.
Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein-ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than -8.0 kcal/mol in the FIXa-grids and higher than -7.5 kcal/mol in the FXa-grids.
血液凝固是止血的重要生理过程；然而，异常的凝血会导致各种潜在致命的疾病，通常被称为血栓栓塞性疾病，这是现代世界死亡的主要原因。最近，FDA 已经批准了几种用于因子 Xa (FXa) 的抗凝药物，这些药物通过凝血级联的共同途径起作用。这些药物的一个主要副作用是患者出血的潜在风险。凝血因子 IXa (FIXa) 最近成为缓解这些风险的战略目标，因为它选择性地调节内在途径。上述凝血因子在结构、功能结构和抑制剂结合模式上非常相似。因此，设计一种可能仅影响 FIXa 的选择性抑制剂仍然是一个挑战。由于这些两种凝血因子的许多 X 射线共晶结构作为蛋白-配体复合物可用，因此进行了结构比对、分子对接和药效团建模，以得出选择性抑制 FIXa 而非 FXa 的相关标准。在这项研究中，选择了六个配体（三个有效，两个选择性，一个无效）用于 FIXa 抑制，选择了六个有效配体（四个 FDA 批准的药物）用于 FXa。药效团假设提供了发生在结合部位的主要相互作用的分布模式。FXa 抑制剂的任何药效团模式都与 FIXa 抑制剂的任何模式不匹配。基于药效团分析，可以将配体对 FIXa 的选择性定量定义为在 FIXa 网格中低于-8.0 kcal/mol 的对接评分和在 FXa 网格中高于-7.5 kcal/mol 的对接评分。
