6DPT
X-ray crystal structure of AmpC beta-lactamase with nanomolar inhibitor
Summary for 6DPT
| Entry DOI | 10.2210/pdb6dpt/pdb |
| Descriptor | Beta-lactamase, 3-chloro-2-hydroxy-N-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]phenyl}benzene-1-sulfonamide (3 entities in total) |
| Functional Keywords | ampc beta-lacatamase, inhibitor complex, phenolate, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Escherichia coli (strain K12) |
| Total number of polymer chains | 2 |
| Total formula weight | 79969.59 |
| Authors | Singh, I. (deposition date: 2018-06-09, release date: 2018-07-04, Last modification date: 2023-10-11) |
| Primary citation | Lyu, J.,Wang, S.,Balius, T.E.,Singh, I.,Levit, A.,Moroz, Y.S.,O'Meara, M.J.,Che, T.,Algaa, E.,Tolmachova, K.,Tolmachev, A.A.,Shoichet, B.K.,Roth, B.L.,Irwin, J.J. Ultra-large library docking for discovering new chemotypes. Nature, 566:224-229, 2019 Cited by PubMed Abstract: Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D dopamine receptor. PubMed: 30728502DOI: 10.1038/s41586-019-0917-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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