Discovery of novel potential CRBN modulators through structure-based virtual screening and bioassay.

Feng Xiong, Ling-Yun Zhou, Liang Chen, Feng Cao, Shuqun Zhang, Zhili Zuo

Journal of molecular graphics & modelling 2022 Dec

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CRBN protein is an E3 ubiquitin ligase which plays an important role in the ubiquitin-proteasome system of eukaryotic cells. Small molecules can modulate CRBN and induce multiple target proteins to bind with CRBN, which contributes to ubiquitination and degradation of target proteins. Modulating the CRBN protein through small molecules provides a novel idea for treatment of tumors and immune system disease. Due to most of CRBN modulators containing glutarimide skeleton, we aimed to discover novel potent CRBN modulators. In this study, Lipinski's rule and Veber rule, pharmacophore based virtual screening, docking based virtual screening and ADMET screening methods were performed to discover potential CRBN modulators. The antitumor activity of 11 candidates were evaluated by MTS assay. AN7535 showed potent antitumor activity with IC50 = 0.72 μM against HL-60 and IC50 = 1.438 μM against SMMC-7721. AO6355 showed potent antitumor activity with IC50 = 7.469 μM against SMMC-7721. MD simulations and binding free energy calculations suggested that AN7535 and AO6355 could stabilize the CRBN protein and have favorable binding affinity with CRBN protein. Luciferase complementation assay suggested AN7535 could bind to CRBN with IC50 = 215.9 μM. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Feng Xiong, Ling-Yun Zhou, Liang Chen, Feng Cao, Shuqun Zhang, Zhili Zuo. Discovery of novel potential CRBN modulators through structure-based virtual screening and bioassay. Journal of molecular graphics & modelling. 2022 Dec;117:108325