Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

Journal Article · Tue Oct 09 04:00:00 EDT 2012 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm200807m· OSTI ID:1040910

Plechanovová, Anna; Byun, Youngjoo; Alquicer, Glenda; Škultétyová, L; ubica,; Ml,; ochová, Petra; N,; mcová, Adriana; Kim, Hyung-Joon; Navrátil, Michal; Mease, Ronnie; Lubkowski, Jacek; Pomper, Martin; Konvalinka, Jan; Rulíšek, Lubomír; Ba,; inka, Cyril ^[1]

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1. NCI

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: FOREIGNNIHNCI
• OSTI ID: 1040910
• Journal Information: J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (21) ; 11, 2011 Vol. 54; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AFFINITY
CARBOXYPEPTIDASES
CHAINS
CRYSTAL STRUCTURE
DESIGN
MOLECULAR WEIGHT
MUTANTS
PLASTICITY
POLAR COMPOUNDS
SPECIFICITY
SUBSTRATES