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Screening of a novel fragment library with functional complexity against Mycobacterium tuberculosis InhA

DOI: 10.1002/cmdc.201700774 DOI Help

Authors: Federica Prati (University of Dundee; GlaxoSmithKline) , Fabio Zuccotto (University of Dundee) , Daniel Fletcher (University of Dundee) , Maire A. Convery (GlaxoSmithKline) , Raquel Fernandez-Menendez (GlaxoSmithKline) , Robert Bates (GlaxoSmithKline) , Lourdes Encinas (GlaxoSmithKline) , Jingkun Zeng (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Paco De Dios Anton (GlaxoSmithKline) , Alfonso Mendoza-Losana (GlaxoSmithKline) , Claire Mackenzie (University of Dundee) , Simon R. Green (University of Dundee) , Margaret Huggett (University of Dundee) , David Barros (GlaxoSmithKline) , Paul G. Wyatt (University of Dundee) , Peter C. Ray (University of Dundee)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 12279

Open Access Open Access

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.

Journal Keywords: Fragment based drug discovery; InhA; Tuberculosis; Functional group complexity

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 15/02/2018 09:14


Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)