title: Prolyl oligopeptidase inhibition by N-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.
authors.affiliation: CHINOIN, Ltd, H-1045 Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Kánai
authors.forename: Péter
authors.initials: P
authors.lastname: Arányi
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Böcskei
authors.forename: György
authors.initials: G
authors.lastname: Ferenczy
authors.forename: Veronika
authors.initials: V
authors.lastname: Harmat
authors.forename: Kálmán
authors.initials: K
authors.lastname: Simon
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátori
authors.forename: Gábor
authors.initials: G
authors.lastname: Náray-Szabo
authors.forename: István
authors.initials: I
authors.lastname: Hermecz
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases