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On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations.
- Source :
-
Journal of chemical information and modeling [J Chem Inf Model] 2023 Apr 24; Vol. 63 (8), pp. 2382-2392. Date of Electronic Publication: 2023 Apr 10. - Publication Year :
- 2023
-
Abstract
- 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 neosubstrate proteins to the E3 ubiquitin ligase cereblon (CRBN) for poly-Lys48-ubiquitination and proteasomal degradation. Ternary complex structures of clinical CELMoDs CC-885 and CC-90009 bound to CRBN and neosubstrate G1 to S phase transition protein 1 (GSPT1) have been experimentally determined. 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 neointerface and correlation to measured cellular degradation for the neosubstrates GSPT1 and zinc finger Aiolos (IKZF3). For a congeneric series of CELMoDs, which have a similar sequence of binding events and resultant binding modes, we conclude that well-established structure-based methods that measure in silico ternary complex stabilities can predict relative degradation potency by CELMoDs.
Details
- Language :
- English
- ISSN :
- 1549-960X
- Volume :
- 63
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of chemical information and modeling
- Publication Type :
- Academic Journal
- Accession number :
- 37037192
- Full Text :
- https://doi.org/10.1021/acs.jcim.2c01386