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2g8n
From Proteopedia
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| , resolution 2.150Å | |||||||
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| Ligands: | and | ||||||
| Activity: | Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy
Contents |
Overview
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.
Disease
Known diseases associated with this structure: Hypertension, essential, 145500 (1) OMIM:[171190]
About this Structure
2G8N is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase., Grunewald GL, Seim MR, Regier RC, Martin JL, Gee CL, Drinkwater N, Criscione KR, J Med Chem. 2006 Sep 7;49(18):5424-33. PMID:16942016
Page seeded by OCA on Thu Mar 20 17:01:44 2008
