2g8n
From Proteopedia
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Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy
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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 with F83 and SAH as ligands. Active as Phenylethanolamine N-methyltransferase, with EC number 2.1.1.28 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 Mon Nov 12 22:16:11 2007
