Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules
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Tartalom: http://real.mtak.hu/2902/
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published


Type = Article
Cím:
Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules
Létrehozó:
Kánai, Károly
Arányi, Péter
Böcskei, Zsolt
Ferenczy, György
Harmat, Veronika
Simon, Kálmán
Bátori, Sándor
Náray-Szabó, Gábor
Hermecz, István
Dátum:
2008
Téma:
QD04 Organic chemistry / szerves kémia
QH3015 Molecular biology / molekuláris biológia
Tartalmi leírás:
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.
Típus:
Article
PeerReviewed
Formátum:
application/pdf
Azonosító:
Kánai, Károly and Arányi, Péter and Böcskei, Zsolt and Ferenczy, György and Harmat, Veronika and Simon, Kálmán and Bátori, Sándor and Náray-Szabó, Gábor and Hermecz, István (2008) Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules. J Med Chem, 51. pp. 7514-7522.
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