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Disrupting the Constitutive, Homodimeric Protein-Protein Interface in in…

- - - - Mass spectrometry
        
        Homodissociation ITC
        
        Structure-Activity Relationship
        
        Using structural analogs of 4, 16 compounds.
        
        Functional group substitution induce different Kd values.
        
        Mutant CK2β is potentially useful to develop fragments, disrupting dimer CK2β.
        
        Double mutation of Pro110 and Val143 to weaken binding affinity of dimer CK2β.
        
        Out of 18 fragments, 2 showed most potent in mediating dimerization disruption.
        
        18 out of 40 compounds induced a higher population of monomeric CK2β
        
        1 and 2 (5-substituted pyrazole core) had the greatest effects on dimer disruption.
        
        3, 4 (pyrazole scaffold), 5-7 (quinolone), 8-11 (naphthol) show monomerization effect.
        
        No correlation between monomerization and thermal shift.
        
        Through mutation of Zinc-coordinating cysteine residue, Zinc finger is associated with Dimerization.
        
        Fragments do not cause metal sequestration on Zinc finger while disrupting dimer.
        
        Fragments cause distorting and weakening dimer interface.
      - Monitoring differences in the properties of the ligand spectra upon interaction with the macromolecular target.
        
        STD, waterLOGSY, CPMG are commonly used.
        
        Validated 45 of the 60 destabilizing hits, 40 fragments showed binding in all three NMR experiment.
        
        No correlation between the degree of binding observed in the NMR experiment and ∆Tm values.
        
        ∆Tm cannot be used as a measure of its binding affinity and degree of binding in NMR assays.