Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA

• Published in: ChemMedChem Vol. 13; no. 7; pp. 672 - 677
• Main Authors: Prati, Federica, Zuccotto, Fabio, Fletcher, Daniel, Convery, Maire A., Fernandez‐Menendez, Raquel, Bates, Robert, Encinas, Lourdes, Zeng, Jingkun, Chung, Chun‐wa, De Dios Anton, Paco, Mendoza‐Losana, Alfonso, Mackenzie, Claire, Green, Simon R., Huggett, Margaret, Barros, David, Wyatt, Paul G., Ray, Peter C.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 06.04.2018; John Wiley and Sons Inc
• Subjects: Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Communication; Communications; Complexity; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; fragment based drug discovery; Fragmentation; functional group complexity; Functional groups; InhA; Ligands; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Optimization; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - chemistry; Screening; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Surface Plasmon Resonance; Tuberculosis; fragment based drug discovery; InhA; functional group complexity; tuberculosis
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700774

Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization. Functional group complexity fragment hits facilitated rapid fragment‐based lead generation against Mycobacterium tuberculosis InhA, to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.