Discovery of Highly Potent CRBN Ligands and Insight into Their Binding Mode through Molecular Docking and Molecular Dynamics Simulations

Abstract Cereblon (CRBN) is a substrate receptor of E3 ubiquitin ligase as well as the target of thalidomide and lenalidomide, plays a vital role in endogenous protein degradation. In this article, two series of compounds with novel structure were designed, synthesized and evaluated against CRBN. YJ1b, designed based on our previous finding, shown strong binding affinity toward CRBN (IC 50 =0.206 μM) by forming a salt bridge interaction with amino acid residue Glu377 of CRBN, it was 13‐fold compared with that of lenalidomide (IC 50 =2.694 μM) in TR‐FRET assay. YJ2c and YJ2h, two analogs of YJ1b, also exhibit high binding affinity toward CRBN (IC 50 =0.211 μM and IC 50 =0.282 μM, respectively). While, molecular docking and 100 ns molecular dynamic simulation studies were conducted to insight into the unique binding mode of YJ1b, YJ2c and YJ2e toward CRBN. The new compounds with special binding mode in this article may serve for the further optimization and discovery of novel high potent CRBN ligands.