Molecular docking based screening of a simulated HIF-1 protein model for potential inhibitors

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-1 alpha and HIF-1 beta, 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, ARG46 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-1 alpha.