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

• DOI: 10.1002/cmdc.201300219
• Publication Date: 2013-06-20T17:28:18Z
• Authors: Sean A. Hudson; Sachin Surade; Anthony G. Coyne; Kirsty J. McLean; David Leys; Andrew W. Munro; Chris Abell
• Keywords: 0303 health sciences; Binding Sites; Drug discovery; Fragment-based; Hydrogen Bonding; Mycobacterium tuberculosis; Triazoles; Crystallography, X-Ray; Ligands; Communications; 3. Good health; 03 medical and health sciences; Bacterial Proteins; Cytochrome P-450 Enzyme System; Catalytic Domain; Drug Design; Conformation analysis; Cytochromes; Tuberculosis; Enzyme Inhibitors; Protein Binding

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.[Image: see text]