@article{6795a54f868743c2ab13083fc6861f43,
title = "Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors",
abstract = "A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized using ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-L-glutamic acid, as a molecular template in order to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPII inhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII's preference for peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealed that ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt a nearly identical binding mode while (R,S)-carbamate analog 8 containing a D-leucine forms a less extensive hydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPII active site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 and compound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the protein active site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscore a broader range of factors that need to be taken into account in predicting ligand-protein binding affinity. These insights should be of particular importance in future efforts to design and develop GCPII inhibitors for optimal inhibitory potency.",
keywords = "Crystal structure, Glutamate carboxypeptidase II, Metallopeptidase, Prostate-specific membrane antigen",
author = "Cyril Barinka and Zora Novakova and Niyada Hin and Daniel B{\'i}m and Ferraris, {Dana V.} and Bridget Duvall and Gabriel Kabarriti and Reiji Tsukamoto and Milos Budesinsky and Lucia Motlova and Camilo Rojas and Slusher, {Barbara S.} and Rokob, {Tibor Andr{\'a}s} and Lubom{\'i}r Rul{\'i}{\v s}ek and Takashi Tsukamoto",
note = "Funding Information: We acknowledge Iva Jelinkova, Barbora Havlinova, and Petra Baranova for the excellent technical assistance and DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the use of experimental facilities. Parts of this research were carried out at the PETRA III storage ring and we thank Isabel Bento for assistance in using the P13 beamline. This work was in part supported by the CAS (RVO: 86652036), MEYS CR (LM2015043 CIISB), and projects CIISB4HEALTH (CZ.02.1.01/0.0/0.0/16_013/0001776) and BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF and by NIH grants R01CA161056 and P30MH075673 awarded to BSS. LR acknowledges the support from Grant Agency of the Czech Republic (grant 17-24155S ) and computer time at IT4I infrastructure ( MEYS grant LM2015070 , Large Infrastructures for Research, Experimental Development and Innovations: IT4Innovations National Supercomputing Center). Funding Information: We acknowledge Iva Jelinkova, Barbora Havlinova, and Petra Baranova for the excellent technical assistance and DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the use of experimental facilities. Parts of this research were carried out at the PETRA III storage ring and we thank Isabel Bento for assistance in using the P13 beamline. This work was in part supported by the CAS (RVO: 86652036), MEYS CR (LM2015043 CIISB), and projects CIISB4HEALTH (CZ.02.1.01/0.0/0.0/16_013/0001776) and BIOCEV (CZ.1.05/1.1.00/02.0109) from the ERDF and by NIH grants R01CA161056 and P30MH075673 awarded to BSS. LR acknowledges the support from Grant Agency of the Czech Republic (grant 17-24155S) and computer time at IT4I infrastructure (MEYS grant LM2015070, Large Infrastructures for Research, Experimental Development and Innovations: IT4Innovations National Supercomputing Center). Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",
year = "2019",
month = jan,
day = "15",
doi = "10.1016/j.bmc.2018.11.022",
language = "English (US)",
volume = "27",
pages = "255--264",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "2",
}