Molecular glues are small molecules that simultaneously bind to two proteins, creating a chemically induced protein-protein interface. CELMoDs (Cereblon E3 Ligase Modulators) are a class of molecular glues that promote recruitment of substrate proteins to the E3 ubiquitin ligase cereblon (CRBN) for ubiquitination and proteasomal degradation. The ternary complex structure of clinical CELMoDs CC-885 and CC-90009 bound to CRBN and neo-substrate protein G1 to S phase transition 1 (GSPT1) were previously disclosed. Although cellular degradation is a downstream event, dependent not only on the affinity of the glue CELMoD in the ternary complex, we test the applicability of established structure based drug design principles to predict binding affinity of CELMoDs to the protein-protein neo-interface and correlation to measured cellular degradation for the neo-substrates GSPT1 and zinc finger Aiolos (IKZF3). We show that well-established methods such as docking, free energy perturbation (FEP) and symmetry adapted perturbation theory (SAPT) can predict relative degradation potency by CELMoDs.

Structure based drug design for prediction of molecular glue degradation potency

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ACS Fall 2022

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