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6DPX

X-ray crystal structure of AmpC beta-lactamase with inhibitor

Summary for 6DPX
Entry DOI10.2210/pdb6dpx/pdb
DescriptorBeta-lactamase, (3-{[(3-chloro-2-hydroxyphenyl)sulfonyl]amino}phenyl)acetic acid (3 entities in total)
Functional Keywordsampc beta-lacatamase, inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceEscherichia coli (strain K12)
Total number of polymer chains2
Total formula weight79859.38
Authors
Singh, I. (deposition date: 2018-06-09, release date: 2018-07-04, Last modification date: 2023-10-11)
Primary citationLyu, 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: 30728502
DOI: 10.1038/s41586-019-0917-9
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.9 Å)
Structure validation

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