Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA. (19th February 2018)

• Record Type: Journal Article
• 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.
• Is Part Of: ChemMedChem. Volume 13:Number 7(2018)
• Page Start: 672
• Page End: 677
• Publication Date: 2018-02-19
• Subjects: fragment based drug discovery -- functional group complexity -- InhA -- tuberculosis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700774
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : 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.