Abstract
Hypoxia inducible factor-1(HIF-1) is a bHLH-family transcription factor that control genes involved in glucolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a hetero dimer of HIF-1α and HIF-1β, binds to the hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). It is one the molecular target for angiogenesis. A series of Chalcone - like compounds described that preferentially inhibit HIF-1 dimer, which can interact with amino acids within the active site of the protein. It is of interest model the HIF-1 dimer protein and protein was subjected to molecular dynamics simulations using NAMD 2.9 software with CHARMM27 force field in water and the protein structure was minimized with 25000 steps for 500 ps and simulation with 1000000 steps for 2ns. 2500 compounds were screened from Zinc database through structure based virtual screening with references to Chalcone natural drug compound. The screened compounds were docked into the active site of the protein using AutoDock Vina in PyRx Virtual screening tool. The docking result showed the compounds Zinc04280532, Zinc04280533, Zinc04280469, Zinc04280534, Zinc16405915, Zinc04277060, Zinc04280538, Zinc04582923, Zinc05280554 and Zinc05943723 have high binding affinities then query compound. The lead hit compounds were also testing for toxicity and bioavailability using Osiris and Molinspiration online server. The active site amino acids such as TYR-21, ASN-34, VAL-35, MET-18, LYS-17, SER-36, ARG- 46 and ARG-14 are key role in the inhibitors activity. This is useful in the design of small molecule therapeutics or the treatment of different abnormalities associated with impaired HIF-1α.
Highlights
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels
The most important mediator identified in this pathway is hypoxia inducible factor-1 (HIF-1), a transcription factor for various angiogenic factors such as vascular endothelial growth factor (VEGF), and for genes encoding proteins involved in energy metabolism, cell survival, red blood cell production, and vasomotor regulation [4]
In HIF-1α, the N-terminal domain is required for dimerization and DNA binding, whereas the C-terminal domains are required for hypoxia-induced nuclear localization, protein stabilization and transactivation [6,7]
Summary
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. This is distinct from vasculogenesis, which is the de novo formation of endothelial cells [1] from mesoderm cell precursors. The most important mediator identified in this pathway is hypoxia inducible factor-1 (HIF-1), a transcription factor for various angiogenic factors such as vascular endothelial growth factor (VEGF), and for genes encoding proteins involved in energy metabolism, cell survival, red blood cell production, and vasomotor regulation [4]. In HIF-1α, the N-terminal (bHLHPAS) domain is required for dimerization and DNA binding, whereas the C-terminal domains are required for hypoxia-induced nuclear localization, protein stabilization and transactivation [6,7]. The two subunits bind with a specific five-nucleotide DNA sequence (5′-RCGTG-3′), known as the hypoxia responsive element (HRE), located in the promoter regions of hypoxia-responsive genes [7]
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