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

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

doi:10.3389/fphar.2020.579768

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

Front Pharmacol. 2020 Nov 11:11:579768. doi: 10.3389/fphar.2020.579768. eCollection 2020.

Authors

Yuwei Wang^{1

2}, Shuai Tang³, Huanling Lai², Ruyi Jin¹, Xu Long¹, Na Li¹, Yuping Tang¹, Hui Guo¹, Xiaojun Yao², Elaine Lai-Han Leung²

Affiliations

¹ College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academic of Sciences, Shanghai, China.

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 aIDH1^R132H 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 IDH1^R132H inhibitors from a decoy set, a docking-based virtual screening strategy was employed for identifying new IDH1^R132H inhibitors. In the end, 57 structurally diverse compounds were reserved and evaluated through experimental tests, and 10 of them showed substantial activity in targeting IDH1^R132H (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.

Keywords: IDH1; docking-based virtual screening; gliomas; molecular docking; virtual screening.