Inhibition of the HSP90 homodimerization and HSP90-HIF1α interactions by employing small molecules at C-terminal ATP binding site of HSP90

Abstract

AbstractThe Heat shock protein HSP 90-alpha (HSP90AA1) is a major chaperone that stabilizes the hypoxia-inducible factor 1α under hypoxic stress and develops solid tumors. Recent studies revealed that in addition to N-terminal ATP binding site, HSP90 has an additional ATP binding site at the C-terminal end. So, disruption of HSP90 and HIF 1 α interaction is an innovative method to control cancer progression. This can be achieved by employing small molecules at C-terminal ATP-binding that do not affect the overall functioning of the HSP90. But there is a lack of structural basis for HIF-1α and HSP90AA1 interactions. This study screened natural products and their derivatives against HSP90AA1 and HIF-1α interaction disruption. Virtual screening was carried out using Glide. We found that compounds with indole rings bind to the C-terminal ATP binding site of HSP90 and prevent its interaction with HIF-1α. Tryptamine derivatives with indole rings showed a greater binding affinity than other molecules. Thus, Tryptamine hydrochloride compounds can be used as a drug repurposing approach to treat hypoxic tumors.Abstract Figure