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

Abstract

The Heat shock protein HSP 90-alpha (HSP90AA1) is a major chaperone that stabilizes the hypoxia-inducible factor 1 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 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-1 and HSP90AA1 interactions. This study screened natural products and their derivatives against HSP90AA1 and HIF-1 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-1. 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/595921v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d2d547org.highwire.dtl.DTLVardef@b03175org.highwire.dtl.DTLVardef@17f0d31org.highwire.dtl.DTLVardef@3b30a2_HPS_FORMAT_FIGEXP M_FIG C_FIG