7UP2

NDM1-inhibitor co-structure

Summary for 7UP2

• Entry DOI: 10.2210/pdb7up2/pdb
• Descriptor: Beta-lactamase VIM-1, ZINC ION, (2M)-4'-methyl-2-(2H-tetrazol-5-yl)[1,1'-biphenyl]-3-sulfonamide, ... (4 entities in total)
• Functional Keywords: metallo-beta-lactamase inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 26455.97

Authors

Scapin, G.,Fischmann, T.O. (deposition date: 2022-04-14, release date: 2023-03-08, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.13 Å)