Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
Department of Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran.
Proteins. 2023 Apr;91(4):542-554. doi: 10.1002/prot.26448. Epub 2022 Dec 2.
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.
肝素和硫酸乙酰肝素是重要的糖胺聚糖，可调节许多重要蛋白质的活性，尤其是成纤维细胞生长因子（FGF）家族。由于 FGF7（KGF）在组织修复和维持黏膜屏障完整性方面具有重要作用，重组人角质细胞生长因子（rhKGF，培洛昔芬）已被批准用于治疗伤口愈合和口腔。由于肝素在 KGF 信号通路中发挥重要作用，因此有必要在原子水平上更详细地研究 rhKGF 与肝素之间的药物相互作用（DDI），并从生物学角度特别是在计算机上研究它们之间的协同作用，以便更好地理解 DDI。在这项研究中，研究了 rhKGF 与低分子量肝素（LMWH）之间的 DDI。在这方面，通过分子对接和分子动力学模拟（MDs）等计算方法来仔细研究协同肝素类型对 rhKGF 的结构和生物稳定性的影响。随后，通过主成分分析（PCA）基于特征向量评估 rhKGF 与 LMWH 相互作用的运动行为。此外，还通过分子力学/泊松-玻尔兹曼表面面积（MM-BPSA）方法计算了 rhKGF-LMWH 复合物的结合自由能。结果表明，rhKGF-idraparinux（-6.9 kcal/mol）和 rhKGF-heparin（-6.0 kcal/mol）复合物具有显著的结合亲和力，并且在 100 ns 模拟过程中它们与 rhKGF 的结合比与其他 LMWH 更稳定。然而，为了确认这些药物的疗效，必须进行临床试验。
