8u0q | pdb_00008u0q

Co-crystal structure of optimized analog TDI-13537 provided new insights into the potency determinants of the sulfonamide inhibitor series

spinqualitylabelsall models 8u0q, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u0q is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.69Å Ligands: FAD, GOL, U4I Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DLDH_MYCTU Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro. Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system. Appears to be essential for Mtb pathogenesis. Publication Abstract from PubMed Lpd (lipoamide dehydrogenase) in Mycobacterium tuberculosis (Mtb) is required for virulence and is a genetically validated tuberculosis (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series have been identified. Recent advances in large-scale virtual screening methods combined with make-on-demand compound libraries have shown the potential for finding novel hits. In this study, the Enamine REAL library consisting of approximately 1.12 billion compounds was efficiently screened using the GPU Shape screen method against Mtb Lpd to find additional chemical matter that would expand on the known sulfonamide inhibitor series. We identified six new inhibitors with IC(50) in the range of 5-100 muM. While these compounds remained chemically close to the already known sulfonamide series inhibitors, some diversity was found in the cores of the hits. The two most potent hits were further validated by one-step potency optimization to submicromolar levels. The co-crystal structure of optimized analogue TDI-13537 provided new insights into the potency determinants of the series. Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors.,Michino M, Beautrait A, Boyles NA, Nadupalli A, Dementiev A, Sun S, Ginn J, Baxt L, Suto R, Bryk R, Jerome SV, Huggins DJ, Vendome J ACS Bio Med Chem Au. 2023 Sep 8;3(6):507-515. doi: , 10.1021/acsbiomedchemau.3c00046. eCollection 2023 Dec 20. PMID:38144256 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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