Discovery of novel inhibitors disrupting HIF-1α/von Hippel-Lindau interaction through shape-based screening and cascade docking.

Xin Xue,Yuan Sun,Chen Kang,Hai-Tao Yu,Ning-Yi Zhao,Xiao-Long Wang,Nian-Guang Li,Qiong-Bin Huang,Hao-Peng Sun

doi:10.7717/peerj.2757

Abstract

Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel–Lindau interaction.

Highlights

Protein–protein interactions (PPIs) play a crucial role in the cellular function and form the backbones of almost all biochemical processes (Wells & McClendon, 2007)
After the oxygen-dependent enzymatic hydroxylation of proline residues by prolyl hydroxylases (PHD) (Schofield & Ratcliffe, 2004), hypoxia-inducible factor 1α (HIF-1α) tends to be degraded through ubiquitinproteasome system (UPS), which is normally governed by the activity of the complex consisting of the pVHL, elongins B and C, cullin 2, and ring box protein 1 (Rbx1) (Lonser et al, 2003)
Our report has demonstrated a great effort in the optimization of the virtual screening (VS) strategy for protein–protein interactions

Summary

Introduction

Protein–protein interactions (PPIs) play a crucial role in the cellular function and form the backbones of almost all biochemical processes (Wells & McClendon, 2007). One class of PPIs with promising therapeutic potential is the interaction between the hypoxia-inducible factor 1α (HIF-1α) and the von Hippel–Lindau protein (pVHL), which acts as an essential component of a multi-subunit E3 ligase. How to cite this article Xue et al (2016), Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking. After the oxygen-dependent enzymatic hydroxylation of proline residues by prolyl hydroxylases (PHD) (Schofield & Ratcliffe, 2004), HIF-1α tends to be degraded through ubiquitinproteasome system (UPS), which is normally governed by the activity of the complex consisting of the pVHL, elongins B and C, cullin 2, and ring box protein 1 (Rbx1) (Lonser et al, 2003)

Methods

Results

Conclusion