Inhibition of prolyl oligopeptidase with a synthetic unnatural dipeptide

Abstract

The synthesis of a new inhibitor of prolyl oligopeptidase, containing a piperidine ring, together with an X-ray structure of its complex with the enzyme, is described. This provides evidence that covalent inhibitors of POP do not have to be limited to structures containing 5-membered N-containing heterocyclic rings. inhibitor:Leave this area blank for abstract info. Abstract-A new inhibitor, containing a linked proline-piperidine structure, for the enzyme prolyl oligopeptidase (POP) has been synthesised and demonstrated to bind covalently with the enzyme at the active site. This provides evidence that covalent inhibitors of POP do not have to be limited to structures containing 5-membered N-containing heterocyclic rings.

Virtual Screening and Computational Optimization for the Discovery of Covalent Prolyl Oligopeptidase Inhibitors with Activity in Human Cells

“…We have previously found that substituting the five-membered ring with a six-membered ring was detrimental to the inhibitor’s activity (Figure ) . This contrasted with the finding from Racys and co-workers who reported a very active inhibitor built around a piperidine ring . In the present work, the substitution of the pyrrolidine ring of 8 by a piperidine ring ( 9 ) led to a decrease of inhibitory activity.…”

“…22 This contrasted with the finding from Racys and co-workers who reported a very active inhibitor built around a piperidine ring. 39 In the present work, the substitution of the pyrrolidine ring of 8 by a piperidine ring (9) led to a decrease of inhibitory activity.…”

3-Oxo-hexahydro-1H-isoindole-4-carboxylic Acid as a Drug Chiral Bicyclic Scaffold: Structure-Based Design and Preparation of Conformationally Constrained Covalent and Noncovalent Prolyl Oligopeptidase Inhibitors

“…The selection of R 1 and R 2 groups considered the synthetic feasibility. Figure a shows the binding mode of Cbz-Pro-Pip-CN cocrystallized with POP . As with other cocrystallized ligands, this structure revealed two key hydrogen bonds with Arg643 and Trp595, a covalent bond with Ser554 and hydrophobic interactions with Phe173.…”

“…Figure 5a shows the binding mode of Cbz-Pro-Pip-CN cocrystallized with POP. 29 As with other cocrystallized ligands, this structure revealed two key hydrogen bonds with Arg643 and Trp595, a covalent bond with Ser554 and hydrophobic interactions with Phe173. Our compounds were docked and compared to this ligand cocrystallized structure (Figure 5b−f).…”

Molecular Simulation Investigation of Prolyl Oligopeptidase from Pyrobaculum Calidifontis and In Silico Docking With Substrates and Inhibitors

“…the removal of oxalate group and replacement of diethyl amine with acetate group. The structure was designed using structure sketching utility by PubChem [62]. Later on, it was docked with PC-POP, as shown in Figure 11.…”