Abstract：
Heparin and heparan sulfate are important glycosaminoglycans that can regulate the activities of many vital proteins, especially the fibroblast growth factor (FGF) family. Because FGF7 (KGF) has an important role in tissue repair and maintaining the integrity of the mucosal barrier, recombinant human keratinocyte growth factor (rhKGF, palifermin) has been approved for the treatment of wound healing and oral cavity. Due to heparin plays an important role in the KGF signaling pathway, a more detailed study of the drug-drug interactions (DDIs) between rhKGF and heparin at the atomic level and investigating their synergistic effect on each other in terms of biology, especially in silico, is necessary for a better understanding of DDIs. In this study, DDIs between rhKGF and low-molecular weight heparin types (LMWH) were investigated. In this regard, scrutiny of the influence of the synergistic heparin types on the structure and biostability of rhKGF is accomplished using computational methods such as molecular docking and molecular dynamic simulations (MDs). Subsequently, the motion behavior of rhKGF in interaction with LMWHs was evaluated based on eigenvectors by using principal component analysis (PCA). Also, the binding free energies of rhKGF-LMWH complexes were calculated by the molecular mechanics/Poisson-Boltzmann surface area (MM-BPSA) method. The result showed that rhKGF-idraparinux (-6.9 kcal/mol) and rhKGF-heparin (-6.0 kcal/mol) complexes had significant binding affinity as well as they had a more stable binding to rhKGF than to other LMWH during 100 ns simulation. However, in order to confirm the curative effect of these drugs, clinical trials must be done.
摘要：
肝素和硫酸乙酰肝素是重要的糖胺聚糖，可以调节许多重要蛋白质的活性，特别是成纤维细胞生长因子（FGF）家族。由于FGF7（KGF）在组织修复和维持粘膜屏障的完整性方面具有重要作用，重组人角质形成细胞生长因子(rhKGF，palifermin）已被批准用于治疗伤口愈合和口腔。由于肝素在KGF信号通路中起着重要作用,在原子水平上对rhKGF和肝素之间的药物-药物相互作用（DDIs）进行了更详细的研究，并研究了它们在生物学方面的协同作用。尤其是在硅，对于更好地理解DDI是必要的。在这项研究中,研究了rhKGF和低分子量肝素类型(LMWH)之间的DDI。在这方面,使用诸如分子对接和分子动态模拟（MD）的计算方法来完成协同肝素类型对rhKGF的结构和生物稳定性的影响的审查。随后，rhKGF与LMWH相互作用的运动行为是通过主成分分析（PCA）基于特征向量进行评估的。此外，通过分子力学/泊松-玻尔兹曼表面积（MM-BPSA）方法计算了rhKGF-LMWH复合物的结合自由能。结果表明，在100ns模拟期间，rhKGF-idraparinux（-6.9kcal/mol）和rhKGF-肝素（-6.0kcal/mol）复合物具有显着的结合亲和力，并且与rhKGF的结合比与其他LMWH的结合更稳定。然而,为了证实这些药物的疗效，必须进行临床试验。
