Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules

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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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.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
Depositing User: Prof Gábor Náray-Szabó
Date Deposited: 23 Feb 2012 11:00
Last Modified: 08 Oct 2012 11:23

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