7OC7
LasB, alpha-alkyl-N-aryl mercaptoacetamide
Summary for 7OC7
| Entry DOI | 10.2210/pdb7oc7/pdb |
| Descriptor | Neutral metalloproteinase, ZINC ION, (2R)-N,3-diphenyl-2-sulfanyl-propanamide, ... (5 entities in total) |
| Functional Keywords | lasb, alpha-alkyl-n-aryl mercaptoacetamide, hydrolase |
| Biological source | Pseudomonas aeruginosa |
| Total number of polymer chains | 1 |
| Total formula weight | 33422.16 |
| Authors | Koehnke, J.,Sikandar, A. (deposition date: 2021-04-26, release date: 2022-01-19, Last modification date: 2024-11-13) |
| Primary citation | Kaya, C.,Walter, I.,Yahiaoui, S.,Sikandar, A.,Alhayek, A.,Konstantinovic, J.,Kany, A.M.,Haupenthal, J.,Kohnke, J.,Hartmann, R.W.,Hirsch, A.K.H. Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors. Angew.Chem.Int.Ed.Engl., 61:e202112295-e202112295, 2022 Cited by PubMed Abstract: Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates. PubMed: 34762767DOI: 10.1002/anie.202112295 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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