Open AccessStructure-Based Drug Design of Bisubstrate Inhibitors of Phenylethanolamine N-Methyltransferase Possessing Low Nanomolar Affinity at Both Substrate Binding Domains1
Author(s) -
Jian Lü,
Aaron G. Bart,
Qian Wu,
Kevin R. Criscione,
Michael J. McLeish,
Emily E. Scott,
Gary L. Grunewald
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01475
Subject(s) - phenylethanolamine n methyltransferase , phenylethanolamine , chemistry , substrate (aquarium) , enzyme , stereochemistry , mutagenesis , enzyme inhibitor , chemical synthesis , binding site , methyltransferase , biochemistry , in vitro , mutation , dna , oceanography , tyrosine hydroxylase , methylation , geology , gene
The enzyme phenylethanolamine N -methyltransferase (PNMT, EC 2.1.1.28) catalyzes the final step in the biosynthesis of epinephrine and is a potential drug target, primarily for the control of hypertension. Unfortunately, many potent PNMT inhibitors also possess significant affinity for the a 2 -adrenoceptor, which complicates the interpretation of their pharmacology. A bisubstrate analogue approach offers the potential for development of highly selective inhibitors of PNMT. This paper documents the design, synthesis, and evaluation of such analogues, several of which were found to possess human PNMT (hPNMT) inhibitory potency <5 nM versus AdoMet. Site-directed mutagenesis studies were consistent with bisubstrate binding. Two of these compounds ( 19 and 29 ) were co-crystallized with hPNMT and the resulting structures revealed both compounds bound as predicted, simultaneously occupying both substrate binding domains. This bisubstrate inhibitor approach has resulted in one of the most potent ( 20 ) and selective (vs the a 2- adrenoceptor) inhibitors of hPNMT yet reported.