ArticleJournal of medicinal chemistry2011
Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Halogen Replacement on the Lysine Side Chain of Lys-Urea-Glu-Based PSMA Inhibitors Leads to Significant Changes in Targeting Properties.Molecular imaging and biology · 2023Article
- Combination ofJournal of chemical information and modeling · 2023Article
- Metamorphosis of prostate specific membrane antigen (PSMA) inhibitors.Biophysical reviews · 2022Review
- Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?EJNMMI radiopharmacy and chemistry · 2021Article
- Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors.Bioorganic & medicinal chemistry · 2019Article
- Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities.The FEBS journal · 2016Article
- ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs.The Journal of biological chemistry · 2015Article
- Structural characterization of P1'-diversified urea-based inhibitors of glutamate carboxypeptidase II.Bioorganic & medicinal chemistry letters · 2014Article
- Synthesis and Biological Evaluation of Substrate-Based Imaging Agents for the Prostate-Specific Membrane Antigen.Macromolecular research · 2013Article
- Development of a high-throughput fluorescence polarization assay to identify novel ligands of glutamate carboxypeptidase II.Journal of biomolecular screening · 2012Article
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.