Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening.

Yuwei Wang,Huanling Lai,Yuping Tang,Hui Guo,Na Li,Elaine Lai-Han Leung,Ruyi Jin,Shuai Tang,Xiaojun Yao,Xu Long

doi:10.3389/fphar.2020.579768

Abstract

IDH1 mutations occur in about 20–30% of gliomas and are a promising target for the treatment of cancer. In the present study, the performance of aIDH1R132H was verified via glide-docking-based virtual screening. On the basis of the two crystal structures (5TQH and 6B0Z) with the best discriminating ability to identify IDH1R132H inhibitors from a decoy set, a docking-based virtual screening strategy was employed for identifying new IDH1R132H inhibitors. In the end, 57 structurally diverse compounds were reserved and evaluated through experimental tests, and 10 of them showed substantial activity in targeting IDH1R132H (IC50 < 50 μM). Molecular docking technology showed that L806-0255, V015-1671, and AQ-714/41674992 could bind to the binding pocket composed of hydrophobic residues. These findings indicate that L806-0255, V015-1671, and AQ-714/41674992 have the potential as lead compounds for the treatment of IDH1-mutated gliomas through further optimization.

Highlights

Isocitrate dehydrogenase 1 (IDH1) is a critical metabolic enzyme involved in the tricarboxylic acid cycle
As a significant indicator of the docking reliability, docking power was used to reveal the binding pose of the experiment between small molecules and proteins, which was mainly evaluated after redocking with the root-mean-square deviation (RMSD) value of the docking pose and native pose of the small molecule in the IDH1R132H complex
For each IDH1R132H complex, after the native inhibitor was separated from the corresponding complex and preprepared, it was redocked into the original binding site

Summary

INTRODUCTION

Isocitrate dehydrogenase 1 (IDH1) is a critical metabolic enzyme involved in the tricarboxylic acid cycle. AG-120 as the only mutant IDH1 inhibitor in clinic approved by the FDA that has shown encouraging clinical benefits with a total overall response rate of 42% for advanced hematological malignancies (Foran et al, 2019) In light of these encouraging finding, we employed docking-based virtual screening to identify active hits with novel skeleton for targeting mutant IDH1. In 2017, Zheng et al discovered a natural product, clomifene, as an effective inhibitor against the IDH1R132H mutant with a Kd value of 18.45 mM by using docking-based virtual screening (PDB: 4UMX) (Zheng et al, 2017) They proved that clomifene selectively inhibits mutant IDH1 activities in vitro and in vivo models.

MATERIALS AND METHODS

RESULTS AND DISCUSSION

CONCLUSIONS

DATA AVAILABILITY STATEMENT