6DPT

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

6DPT の概要

• エントリーDOI: 10.2210/pdb6dpt/pdb
• 分子名称: 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)
• 機能のキーワード: ampc beta-lacatamase, inhibitor complex, phenolate, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli (strain K12)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79969.59

構造登録者

Singh, I. (登録日: 2018-06-09, 公開日: 2018-07-04, 最終更新日: 2023-10-11)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (1.79 Å)