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Fragment-based design of Mycobacterium tuberculosis InhA inhibitors

DOI: 10.1021/acs.jmedchem.0c00007 DOI Help

Authors: Mohamad Sabbah (University of Cambridge) , Vitor Mendes (University of Cambridge) , Robert G Vistal (University of Cambridge) , David M. G. Dias (University of Cambridge) , Monika Záhorszká (Comenius University in Bratislava) , Katarína Mikušová (Comenius University in Bratislava) , Jana Korduláková (Comenius University in Bratislava) , Anthony G Coyne (University of Cambridge) , Tom L. Blundell (University of Cambridge) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: April 2020
Diamond Proposal Number(s): 9537 , 14043

Open Access Open Access

Abstract: Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library is described and development of the fragment hits using a fragment growing strategy was employed which led to the development InhA inhibitors with affinities of up to 250 nM.

Journal Keywords: Tuberculosis; Mycobacterium tuberculosis; fragment-based drug discovery; fragment- growing; InhA

Diamond Keywords: Tuberculosis (TB); Bacteria

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

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

Added On: 06/04/2020 13:26


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)