Prolyl Oligopeptidase Inhibition byN-Acyl-pro-pyrrolidine-type Molecules

Abstract

Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.

Low molecular weight inhibitors of Prolyl Oligopeptidase: a review of compounds patented from 2003 to 2010

“…Proline, proline derivatives [58,60,[65][66][67][68][69] or natural a-amino acids, both neutral and charged, are fitted [70][71][72]. Moreover, a wide variety of cyclic or bicyclic scaffolds are compatible [73][74][75] while open chains can also be fitted.…”

P2-SubstitutedN-Acylprolylpyrrolidine Inhibitors of Prolyl Oligopeptidase: Biochemical Evaluation, Binding Mode Determination, and Assessment in a Cellular Model of Synucleinopathy

“…In an ongoing effort to design new generations of PREP inhibitors with improved activity, selectivity, and biopharmaceutical profile, we studied PREP–inhibitor complex crystal structures reported in the literature and present in the PDB . In all of these structures, there is space to introduce substituents in the P2 position that could extend beyond the S2 binding site to probe hitherto unexplored regions of the enzyme.…”

Transition-Metal-Free Direct C–H Arylation of Quinoxalin-2(1H)-ones with Diaryliodonium Salts at Room Temperature

“…Among all nitrogen-containing heterocycles, the quinoxalin-2­(1 H )-one skeleton, in particular, is widely distributed in an enormous range of compounds (Figure ). As an important subclass, most compounds featuring the 3-arylquinoxalin-2­(1 H )-one scaffold have biological activities; examples include aldose reductase inhibitors, FXa coagulation inhibitors, PDGF inhibitors, VEGF inhibitors, prolyl oligopeptidase inhibitors, SCD inhibitors, CDK, 1,2,4,6 inhibitors, STK33 inhibitors, antitumor agents/antimicrobials, and CFTR activators . In addition, 3-arylquinoxalin-2­(1 H )-one polymers can act as semiconductors in the field of materials science .…”