Structural and computational basis for potent inhibition of glutamate carboxypeptidase II by carbamate-based inhibitors. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Barinka, Cyril; Novakova, Zora; Hin, Niyada; Bím, Daniel; Ferraris, Dana V.; Duvall, Bridget; Kabarriti, Gabriel; Tsukamoto, Reiji; Budesinsky, Milos; Motlova, Lucia; Rojas, Camilo; Slusher, Barbara S.; Rokob, Tibor András; Rulíšek, Lubomír; Tsukamoto, Takashi
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 2(2019)
• Page Start: 255
• Page End: 264
• Publication Date: 2019-01-15
• Subjects: GCPII glutamate carboxypeptidase II -- PSMA prostate-specific membrane antigen -- SAR structure-activity relationship -- NAAG N-acetyl-aspartyl-glutamate -- ZBG zinc-binding group -- QM/MM quantum mechanics/molecular mechanics; Glutamate carboxypeptidase II -- Prostate-specific membrane antigen -- Crystal structure -- Metallopeptidase; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.11.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of carbamate-based inhibitors of glutamate carboxypeptidase II (GCPII) were designed and synthesized usingZJ-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. Compound7 containing a C-terminal 2-oxypentanedioic acid was more potent than compound5 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 thatZJ-43 and its two carbamate analogs5 and7 with the same ( S, S )-stereochemical configuration adopt a nearly identical binding mode while ( R, S )-carbamate analog8 containing ad -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 distinguishZJ-43 from compounds5 and7 and attributed the higher potency ofZJ-43 and compound7 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.