8U0Q
Co-crystal structure of optimized analog TDI-13537 provided new insights into the potency determinants of the sulfonamide inhibitor series
Summary for 8U0Q
| Entry DOI | 10.2210/pdb8u0q/pdb |
| Descriptor | Dihydrolipoyl dehydrogenase, FLAVIN-ADENINE DINUCLEOTIDE, N-(3-acetamidophenyl)-N~2~-[3-(difluoromethyl)-5-methylbenzene-1-sulfonyl]-N~2~-methylglycinamide, ... (5 entities in total) |
| Functional Keywords | virtual screening, tuberculosis, mycobacteria, lipoamide dehydrogenase, inhibitor, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 104611.45 |
| Authors | Dementiev, A.A.,Michino, M.,Vendome, J.,Ginn, J.,Bryk, R.,Olland, A. (deposition date: 2023-08-29, release date: 2024-01-03, Last modification date: 2024-11-13) |
| Primary citation | Michino, M.,Beautrait, A.,Boyles, N.A.,Nadupalli, A.,Dementiev, A.,Sun, S.,Ginn, J.,Baxt, L.,Suto, R.,Bryk, R.,Jerome, S.V.,Huggins, D.J.,Vendome, J. Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors. Acs Bio Med Chem Au, 3:507-515, 2023 Cited by PubMed Abstract: Lpd (lipoamide dehydrogenase) in (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 ∼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 in the range of 5-100 μM. 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 provided new insights into the potency determinants of the series. PubMed: 38144256DOI: 10.1021/acsbiomedchemau.3c00046 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.69 Å) |
Structure validation
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