PMID- 35308862
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230917
IS  - 2041-6520 (Print)
IS  - 2041-6539 (Electronic)
IS  - 2041-6520 (Linking)
VI  - 13
IP  - 7
DP  - 2022 Feb 16
TI  - Salicylate metal-binding isosteres as fragments for metalloenzyme inhibition.
PG  - 2128-2136
LID - 10.1039/d1sc06011b [doi]
AB  - Metalloenzyme inhibitors typically share a common need to possess a metal-binding 
      pharmacophore (MBP) for binding the active site metal ions. However, MBPs can 
      suffer from physicochemical liabilities, impeding the pharmacological properties 
      and drug-likeliness of inhibitors. To circumvent this, problematic features of 
      the MBP can be identified and exchanged with isosteric replacements. Herein, the 
      carboxylic and hydroxyl group of the salicylic acid MBP were replaced and a total 
      of 27 salicylate metal-binding isosteres (MBIs) synthesized. Of these 27 MBIs, at 
      least 12 represent previously unreported compounds, and the metal-binding 
      abilities of >20 of the MBIs have not been previously reported. These salicylate 
      MBIs were examined for their metal-binding features in model complexes, 
      physicochemical properties, and biological activity. It was observed that 
      salicylate MBIs can demonstrate a range of attractive physicochemical properties 
      and bind to the metal in a variety of expected and unexpected binding modes. The 
      biological activity of these novel MBIs was evaluated by measuring inhibition 
      against two Zn(2+)-dependent metalloenzymes, human glyoxalase 1 (GLO1) and matrix 
      metalloproteinase 3 (MMP-3), as well as a dinuclear Mn(2+)-dependent 
      metalloenzyme, influenza H1N1 N-terminal endonuclease (PA(N)). It was observed 
      that salicylate MBIs could maintain or improve enzyme inhibition and selectivity. 
      To probe salicylate MBIs as fragments for fragment-based drug discovery (FBDD), 
      an MBI that showed good inhibitory activity against GLO1 was derivatized and a 
      rudimentary structure-activity relationship was developed. The resulting 
      elaborated fragments showed GLO1 inhibition with low micromolar activity.
CI  - This journal is (c) The Royal Society of Chemistry.
FAU - Jackl, Moritz K
AU  - Jackl MK
AD  - Department of Chemistry and Biochemistry, University of California San Diego 9500 
      Gilman Drive La Jolla CA 92093-0358 USA scohen@ucsd.edu.
FAU - Seo, Hyeonglim
AU  - Seo H
AUID- ORCID: 0000-0002-2527-9293
AD  - Department of Chemistry and Biochemistry, University of California San Diego 9500 
      Gilman Drive La Jolla CA 92093-0358 USA scohen@ucsd.edu.
FAU - Karges, Johannes
AU  - Karges J
AUID- ORCID: 0000-0001-5258-0260
AD  - Department of Chemistry and Biochemistry, University of California San Diego 9500 
      Gilman Drive La Jolla CA 92093-0358 USA scohen@ucsd.edu.
FAU - Kalaj, Mark
AU  - Kalaj M
AD  - Department of Chemistry and Biochemistry, University of California San Diego 9500 
      Gilman Drive La Jolla CA 92093-0358 USA scohen@ucsd.edu.
FAU - Cohen, Seth M
AU  - Cohen SM
AUID- ORCID: 0000-0002-5233-2280
AD  - Department of Chemistry and Biochemistry, University of California San Diego 9500 
      Gilman Drive La Jolla CA 92093-0358 USA scohen@ucsd.edu.
LA  - eng
GR  - R01 AI149444/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20220121
PL  - England
TA  - Chem Sci
JT  - Chemical science
JID - 101545951
PMC - PMC8849047
COIS- S.M.C. is a cofounder of and has an equity interest in Cleave Therapeutics, Forge 
      Therapeutics, and Blacksmith Medicines, companies that may potentially benefit 
      from the research results. S.M.C. also serves on the Scientific Advisory Board 
      for Blacksmith Medicines and serves on the Scientific Advisory Board and receives 
      compensation from Forge Therapeutics. The terms of this arrangement have been 
      reviewed and approved by the University of California, San Diego in accordance 
      with its conflict-of-interest policies.
EDAT- 2022/03/22 06:00
MHDA- 2022/03/22 06:01
PMCR- 2022/01/21
CRDT- 2022/03/21 08:44
PHST- 2021/10/30 00:00 [received]
PHST- 2022/01/12 00:00 [accepted]
PHST- 2022/03/21 08:44 [entrez]
PHST- 2022/03/22 06:00 [pubmed]
PHST- 2022/03/22 06:01 [medline]
PHST- 2022/01/21 00:00 [pmc-release]
AID - d1sc06011b [pii]
AID - 10.1039/d1sc06011b [doi]
PST - epublish
SO  - Chem Sci. 2022 Jan 21;13(7):2128-2136. doi: 10.1039/d1sc06011b. eCollection 2022 
      Feb 16.