Structural Biology and Structure-Activity Relationship Studies

4 Structural Biology and Structure-Activity Relationship Studies 

NPI-0052 represents the case of a natural product that entered the clinic without structural modification through synthesis or semi-synthesis. A growing body of structure-activity relationship (SAR) studies and structural biology data offer clear insights into its naturally optimised molecular design. 

These mechanistic studies reveal NPI-0052 as a minimalist among protea-some inhibitors, in that each atom is used to maximum efficiency for inhibitor binding to the active site followed by the two-step reaction that renders it irreversibly bound. In fact, NPI-0052 clearly exceeds atom-for-atom efficiency of any currently known proteasome inhibitor. 

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