Molecular Docking and Dynamic Simulation Studies of PHD2 Interactions with Gut Siderophores: Implications for HIF-1α Stabilization

In oxygen-deprived conditions cells respond by activating adaptive mechanisms to bolster their survival and protect tissue integrity. A key player in this process is the HIF-1α signaling cascade, meticulously regulated by Prolyl Hydroxylase Domain 2 (PHD2), which plays a central role in orchestrating cellular responses to fluctuating oxygen levels. The primary aim of this investigation is to explore potential PHD2 inhibitors using in-silico methods by employing molecular docking and dynamic simulation techniques. Low molecular-weight secondary metabolites known as Siderophores secreted from gut microbiota were selected and subjected for stringent assessment against PHD2. Molecular docking analysis revealed that Salmochelin SX (-9.527 Kcal/mol), Mycobactin (-9.166 Kcal/mol), Staphyloferrin A (-7.819 Kcal/mol), and Enterobactin (-7.302 Kcal/mol) displayed substantial affinities for the protein, suggesting them as potential inhibitors. Furthermore, Molecular Dynamic Simulation studies unveiled a noteworthy interaction between the metal ion, Fe ²⁺ , and the ligand molecules, indicating enhanced stability in these interactions. The iron-chelating property is a salient characteristic of many siderophores, and in the same lines our in-silico investigations have yielded promising results. However, it is essential to underscore that the validation of this study remains a critical step to substantiate our hypothesis. Further research and experimental investigations are necessary to confirm the practical implications of these findings and to assess the potential of the identified compounds as effective PHD2 inhibitors.