7UP3

NDM1-inhibitor co-structure

7UP3 の概要

• エントリーDOI: 10.2210/pdb7up3/pdb
• 分子名称: Metallo beta-lactamase, CADMIUM ION, ZINC ION, ... (6 entities in total)
• 機能のキーワード: metallo-beta-lactamase inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Klebsiella pneumoniae
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54297.42

構造登録者

Scapin, G.,Fischmann, T.O. (登録日: 2022-04-14, 公開日: 2023-03-08, 最終更新日: 2023-10-25)

主引用文献

Mandal, M.,Xiao, L.,Pan, W.,Scapin, G.,Li, G.,Tang, H.,Yang, S.W.,Pan, J.,Root, Y.,de Jesus, R.K.,Yang, C.,Prosise, W.,Dayananth, P.,Mirza, A.,Therien, A.G.,Young, K.,Flattery, A.,Garlisi, C.,Zhang, R.,Chu, D.,Sheth, P.,Chu, I.,Wu, J.,Markgraf, C.,Kim, H.Y.,Painter, R.,Mayhood, T.W.,DiNunzio, E.,Wyss, D.F.,Buevich, A.V.,Fischmann, T.,Pasternak, A.,Dong, S.,Hicks, J.D.,Villafania, A.,Liang, L.,Murgolo, N.,Black, T.,Hagmann, W.K.,Tata, J.,Parmee, E.R.,Weber, A.E.,Su, J.,Tang, H.
Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.
J.Med.Chem., 65:16234-16251, 2022

PubMed Abstract: With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by , discovered earlier as metallo-beta-lactamase inhibitors, was selected for virtual screening. From these efforts, compound was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by with a pan MBL inhibition profile. In studies, compound in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.

PubMed: 36475645
DOI: 10.1021/acs.jmedchem.2c00766

実験手法

X-RAY DIFFRACTION (1.4 Å)