6S7W

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(5-(Azepan-1-ylsulfonyl)-2-methoxyphenyl)-2-(quinolin-4-yl)acetamide

Summary for 6S7W

• Entry DOI: 10.2210/pdb6s7w/pdb
• Descriptor: Fumarate hydratase class II, ~{N}-[5-(azepan-1-ylsulfonyl)-2-methoxy-phenyl]-2-quinolin-4-yl-ethanamide, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: fumarate hydratase, fumarase, lyase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 201744.66

Authors

Whitehouse, A.J.,Libardo, M.D.,Kasbekar, M.,Brear, P.,Fischer, G.,Thomas, C.J.,Barry, C.E.,Boshoff, H.I.,Coyne, A.G.,Abell, C. (deposition date: 2019-07-07, release date: 2019-09-25, Last modification date: 2024-01-24)

Primary citation

Whitehouse, A.J.,Libardo, M.D.J.,Kasbekar, M.,Brear, P.D.,Fischer, G.,Thomas, C.J.,Barry 3rd, C.E.,Boshoff, H.I.M.,Coyne, A.G.,Abell, C.
Targeting of Fumarate Hydratase fromMycobacterium tuberculosisUsing Allosteric Inhibitors with a Dimeric-Binding Mode.
J.Med.Chem., 62:10586-10604, 2019

PubMed Abstract: With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in (), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against in vitro identified compounds with potent minimum inhibitory concentrations.

PubMed: 31517489
DOI: 10.1021/acs.jmedchem.9b01203

Experimental method

X-RAY DIFFRACTION (1.44 Å)