Analysis of the binding mode of a novel HIF1α inhibitor through molecular modelling.

Hypoxia inducible factor-1 (HIF1) is an important transcription factor related with tumor metastasis. As a subunit of HIF1, HIF1α plays an important role in regulation of the hypoxic response. HIF1α inhibitor could be a promising treatment for certain cancers. In the present study, we try to model the binding mode of the recent reported new series of HIF1α inhibitors with the purpose of further improving the performance of these inhibitors. Molecular docking was first employed to predict the binding modes of the protein-ligand complexes, followed by molecular dynamics simulations and MMGBSA free energy calculations. According to the predicted binding modes, these molecules form two important hydrogen bonds with HIF1α. Moreover, if the molecules could form a stable π-π interaction with HIF1α, the potency of the inhibitors can be greatly improved. Hydrophobic interactions between the molecules and HIF1α are also a key factor, especially the interactions between the hydrophobic groups (benzimidazole) of the molecules and the hydrophobic residues inside the binding cave. Molecular modeling could be a useful method in the future drug design. In this study, our calculation can help to design and develop high potent HIF1α inhibitors in future.