Molecular Recognition of Sub-micromolar Inhibitors by the Epinephrine-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase

Abstract

The crystal structures of human phenylethanolamine N-methyltransferase in complex with S-adenosyl-l-homocysteine (7, AdoHcy) and either 7-iodo-1,2,3,4-tetrahydroisoquinoline (2) or 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (3, LY134046) were determined and compared with the structure of the enzyme complex with 7 and 7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (1, SK&F 29661). The enzyme is able to accommodate a variety of chemically disparate functional groups on the aromatic ring of the inhibitors through adaptation of the binding pocket for this substituent and by subtle adjustments of the orientation of the inhibitors within the relatively planar binding site. In addition, the interactions formed by the amine nitrogen of all three inhibitors reinforce the hypothesis that this functional group mimics the beta-hydroxyl of norepinephrine rather than the amine. These studies provide further clues for the development of improved inhibitors for use as pharmacological probes.

Exploring the active site of phenylethanolamine N-methyltransferase with 3-hydroxyethyl- and 3-hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoquinolines

“…15 The docking of inhibitors into the hPNMT active site was performed on the R-enantiomer as a previous study on 3-hydroxymethyl-7-substituted-THIQs indicated that the R-enantiomer is preferred over the S-in the hPNMT active site. 32 Residues Lys57 and Met258 move within the PNMT active site depending on the hydrophobicity of the 7-substitutent.…”

“…32 Residues Lys57 and Met258 move within the PNMT active site depending on the hydrophobicity of the 7-substitutent. 15 Inhibitors that contain a 7-nitro substituent were docked into the crystal structure of hPNMT co-crystallized with SK&F 29661 (4), 16 whereas inhibitors that possess a 7-bromo substituent were docked into the crystal structure of hPNMT cocrystallized with 7-iodo-THIQ (3). 15 The amino acid residues surrounding the 3-position of the co-crystallized ligands SK&F 29661 (4) and 7-iodo-THIQ (3) remain in similar positions in both crystal structures.…”

“…14 Examination of the recently solved crystal structures of hPNMT co-crystallized with S-adenosyl-L L-homocysteine (AdoHcy) and either 7-iodo-THIQ (3) 15 or SK&F 29661 (4; 7-aminosulfonyl-THIQ) 16 indicated that the active site should be able to accommodate longer 3-hydroxyalkyl groups. Docking of 3-hydroxyethyl-or 3-hydroxypropyl-7-substituted-THIQs into the PNMT active site indicated that the longer 3-hydroxyalkyl chains could bind favorably ( Fig.…”

Exploring the active site of phenylethanolamine N-methyltransferase with 1,2,3,4-tetrahydrobenz[h]isoquinoline inhibitors☆

“…Interactions between the amine group of THIQ inhibitors and Glu219 are known to play a key role in their binding to hPNMT. [20][21][22] The amine group of 11 is predicted to interact with Glu219 in the same manner as that of 6. According to the docking studies with 11, it is apparent that, in order for 8-substituted-THBQs to bind in the active site of hPNMT, a significant shift of Val53 away from the 8-substituent or a shift of the inhibitor in the active site would be required.…”

Inhibitors of phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity

“…26 To help explain the reduced hPNMT inhibitory potency of the 3-trifluoromethyl-THIQs, molecular docking calculations were conducted using AutoDock 3.0 27 and Sybyl 6.9. 28 Compound 5b was docked into the hPNMT active site based on the X-ray crystal structure of hPNMT-2-AdoHcy (Fig.…”