6SQL

Crystal structure of M. tuberculosis InhA in complex with NAD+ and N-(3-(aminomethyl)phenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide

Summary for 6SQL

• Entry DOI: 10.2210/pdb6sql/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ~{N}-[3-(aminomethyl)phenyl]-5-chloranyl-3-methyl-1-benzothiophene-2-sulfonamide, ... (4 entities in total)
• Functional Keywords: inha, nadh-dependent enoyl-[acyl-carrier-protein] reductase, oxidoreductase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 29672.17

Authors

Mendes, V.,Sabbah, M.,Coyne, A.G.,Abell, C.,Blundell, T.L. (deposition date: 2019-09-04, release date: 2020-04-22, Last modification date: 2024-01-24)

Primary citation

Sabbah, M.,Mendes, V.,Vistal, R.G.,Dias, D.M.G.,Zahorszka, M.,Mikusova, K.,Kordulakova, J.,Coyne, A.G.,Blundell, T.L.,Abell, C.
Fragment-Based Design ofMycobacterium tuberculosisInhA Inhibitors.
J.Med.Chem., 63:4749-4761, 2020

PubMed Abstract: Tuberculosis (TB) remains a leading cause of mortality among infectious diseases worldwide. InhA 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 are described, and the development of the fragment hits using a fragment growing strategy was employed, which led to the development of InhA inhibitors with affinities of up to 250 nM.

PubMed: 32240584
DOI: 10.1021/acs.jmedchem.0c00007

Experimental method

X-RAY DIFFRACTION (2.35 Å)