Overcoming the Limitations of Fragment Merging: Rescuing a Strained Merged Fragment Series Targeting <i>Mycobacterium tuberculosis</i> CYP121

Abstract

Freedom to merge: A combination of crystal structure examination and in silico predictions made it possible to overcome the conformational limitations of fragment merging and escape the internal strain in a series of weakly binding merged fragments that target M. tuberculosis CYP121. The insights attained provide a new perspective and guide for prioritizing synthetic efforts toward fragment merging in future and ongoing fragment-based ligand discovery campaigns.