The Von Hippel-Lindau (VHL) E3 ubiquitin ligase is responsible for the degradation of hypoxia-inducible factor 1α (HIF-1α) under hydroxylation. Computer-aided drug design leads to the discovery of HIF-1α mimetics for the stabilization of hydroxylated α subunit of HIF-1α from subsequent proteasomal degradation to improve diabetic wound healing. The protein-protein interaction (PPI) networking confirms the interaction between the VHL—HIF-1α proteins. So, VHL is the potential target to stabilize the HIF-1α. A set of natural compounds as an inhibitor of PPI between VHL—HIF-1α is identified by structure-based virtual screening. The free HIF-1α leads to accelerates wound closure in both normal and diabetic conditions, with a more significant effect being observed in the diabetic condition. The natural products were designed as HIF-1α mimetics through in-silico Pharmacophore modeling followed by structure-based virtual screening and molecular simulation. In the pharmacophore modeling, 2 acceptors and 1 donor pharmacophore are generated. In the virtual screening process, generated pharmacophore gives a data set of natural compounds that have the same pharmacophoric feature. Based on the docking and absorption, distribution, metabolism, elimination, toxicity studies, the potential inhibitor (ZINC ID: ZINC15959407, ZINC12884117) of PPI is identified.
Key words: Natural compounds, HIF-1α, Diabetic wound, Pharmacophore, Virtual screening, Impaired wound healing.
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