Combined scaffold hopping, molecular screening with dynamic simulation to screen potent CRBN ligands

Abstract Thalidomide and its derivatives lenalidomide and pomalidomide, known as immunomodulatory drugs, (IMiDs) bind directly to cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase, resulting in the rapid ubiquitination and degradation of the substrate protein. With the discovery of the protein degradation mechanism of IMiDs, targeted protein degradation mediated by IMiDs via CRBN emerged and developed rapidly for the advantages of overcoming drug resistance and targeting undruggable. To date, almost all CRBN ligands are derived from thalidomide and there are few structural differences between them. Hence, we employed an accurate, effective, and rational approach to screen novel and potential CRBN ligands. In this study, we have built a molecular library by scaffold hopping with thalidomide. ADMET screening, virtual screening, and visual inspection screening were performed step‐by‐step to screen the molecular library and five molecules were hit. Furthermore, docking analysis and a period of 150 ns molecular dynamic (MD) simulation were performed to validate the accuracy of our screen. The docking results showed that molecular A (−10.42 kcal/mol), molecular B (−9.73 kcal/mol), molecular C (−9.25 kcal/mol), molecular D (−9.09 kcal/mol), and molecular E (−10.16 kcal/mol) have lower binding energy than thalidomide (−5.42 kcal/mol), lenalidomide (−5.74 kcal/mol), and pomalidomide (−5.51 kcal/mol). In the MD simulation, all the five screened molecules form key interactions with the active site amino acid residues (Trp380, Trp386, and Trp400) as well as the three marketed IMiDs. Besides, we found and explained that Pro352 was positive for ligand binding to CRBN and Glu377 in reverse, which has not been reported before. We believe that our findings and those five molecules can serve as further optimization of CRBN ligands and development of proteolysis targeting chimeras.