Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors

Bioorganic & medicinal chemistry 27(2), 255 - 264 (2019). doi:10.1016/j.bmc.2018.11.022
A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesizedusing ZJ-43, N-[[[(1S)-1-carboxy-3-methylbutyl]amino]carbonyl]-L-glutamic acid, as a molecular template inorder to better understand the impact of replacing one of the two nitrogen atoms in the urea-based GCPIIinhibitor with an oxygen atom. Compound 7 containing a C-terminal 2-oxypentanedioic acid was more potentthan compound 5 containing a C-terminal glutamic acid (2-aminopentanedioic acid) despite GCPII’s preferencefor peptides containing an N-terminal glutamate as substrates. Subsequent crystallographic analysis revealedthat ZJ-43 and its two carbamate analogs 5 and 7 with the same (S,S)-stereochemical configuration adopt anearly identical binding mode while (R,S)-carbamate analog 8 containing a D-leucine forms a less extensivehydrogen bonding network. QM and QM/MM calculations have identified no specific interactions in the GCPIIactive site that would distinguish ZJ-43 from compounds 5 and 7 and attributed the higher potency of ZJ-43 andcompound 7 to the free energy changes associated with the transfer of the ligand from bulk solvent to the proteinactive site as a result of the lower ligand strain energy and solvation/desolvation energy. Our findings underscorea 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 foroptimal inhibitory potency.
Published by Elsevier, Amsterdam [u.a.]