7up2: Difference between revisions
New page: '''Unreleased structure''' The entry 7up2 is ON HOLD Authors: Description: Category: Unreleased Structures |
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==NDM1-inhibitor co-structure== | |||
<StructureSection load='7up2' size='340' side='right'caption='[[7up2]], [[Resolution|resolution]] 1.13Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7up2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UP2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.13Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NZR:(2M)-4-methyl-2-(2H-tetrazol-5-yl)[1,1-biphenyl]-3-sulfonamide'>NZR</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7up2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7up2 OCA], [https://pdbe.org/7up2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7up2 RCSB], [https://www.ebi.ac.uk/pdbsum/7up2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7up2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9XAY4_PSEAI Q9XAY4_PSEAI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 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 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 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. | |||
Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.,Mandal M, Xiao L, Pan W, Scapin G, Li G, Tang H, Yang SW, Pan J, Root Y, de Jesus RK, Yang C, Prosise W, Dayananth P, Mirza A, Therien AG, Young K, Flattery A, Garlisi C, Zhang R, Chu D, Sheth P, Chu I, Wu J, Markgraf C, Kim HY, Painter R, Mayhood TW, DiNunzio E, Wyss DF, Buevich AV, Fischmann T, Pasternak A, Dong S, Hicks JD, Villafania A, Liang L, Murgolo N, Black T, Hagmann WK, Tata J, Parmee ER, Weber AE, Su J, Tang H J Med Chem. 2022 Dec 22;65(24):16234-16251. doi: 10.1021/acs.jmedchem.2c00766. , Epub 2022 Dec 7. PMID:36475645<ref>PMID:36475645</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7up2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Pseudomonas aeruginosa]] | |||
[[Category: Fischmann TO]] | |||
[[Category: Scapin G]] | |||
Latest revision as of 12:55, 25 October 2023
NDM1-inhibitor co-structureNDM1-inhibitor co-structure
Structural highlights
FunctionPublication Abstract from PubMedWith 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 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 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 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 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. Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.,Mandal M, Xiao L, Pan W, Scapin G, Li G, Tang H, Yang SW, Pan J, Root Y, de Jesus RK, Yang C, Prosise W, Dayananth P, Mirza A, Therien AG, Young K, Flattery A, Garlisi C, Zhang R, Chu D, Sheth P, Chu I, Wu J, Markgraf C, Kim HY, Painter R, Mayhood TW, DiNunzio E, Wyss DF, Buevich AV, Fischmann T, Pasternak A, Dong S, Hicks JD, Villafania A, Liang L, Murgolo N, Black T, Hagmann WK, Tata J, Parmee ER, Weber AE, Su J, Tang H J Med Chem. 2022 Dec 22;65(24):16234-16251. doi: 10.1021/acs.jmedchem.2c00766. , Epub 2022 Dec 7. PMID:36475645[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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