Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules.
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.
Kánai
Károly
K
CHINOIN, Ltd, H-1045 Budapest, Hungary.
Arányi
Péter
P
Böcskei
Zsolt
Z
Ferenczy
György
G
Harmat
Veronika
V
Simon
Kálmán
K
Bátori
Sándor
S
Náray-Szabo
Gábor
G
Hermecz
István
I
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
D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases