2G8N

Structure of hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy

Summary for 2G8N

• Entry DOI: 10.2210/pdb2g8n/pdb
• Related: 1HNN 1N7J 1NJI 1YZ3 2AN3 2AN4
• Descriptor: Phenylethanolamine N-methyltransferase, (3R)-N-(4-CHLOROPHENYL)-3-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: methyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65166.43

Authors

Drinkwater, N.,Gee, C.L.,Martin, J.L. (deposition date: 2006-03-02, release date: 2006-09-12, Last modification date: 2024-10-23)

Primary citation

Grunewald, G.L.,Seim, M.R.,Regier, R.C.,Martin, J.L.,Gee, C.L.,Drinkwater, N.,Criscione, K.R.
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
J.Med.Chem., 49:5424-5433, 2006

PubMed Abstract: 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.

PubMed: 16942016
DOI: 10.1021/jm060466d

Experimental method

X-RAY DIFFRACTION (2.15 Å)