Structure-Based Design, Synthesis, and in vitro Evaluation of Bisubstrate Inhibitors for CatecholO-Methyltransferase (COMT)

Masjost, Birgit; Ballmer, Patrick; Borroni, Edilio; Zürcher, Gerhard; Winkler, Fritz K.; Jakob‐Roetne, Roland; Diederich, François

doi:10.1002/(sici)1521-3765(20000317)6:6<971::aid-chem971>3.0.co;2-0

Cited by 62 publications

(50 citation statements)

References 19 publications

(35 reference statements)

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“…The interest in COMT as a therapeutic target for Parkinson's disease and the limited beneficial effects observed in parkinsonian patients with tolcapone (liver toxicity) and entacapone (low efficacy) has led to the search and development of other inhibitor molecules that could be clinically useful (Perez et al, 1992;Brevitt and Tan, 1997;Masjost et al, 2000). BIA 3-335 was recently developed as a potent and selective COMT inhibitor (Learmonth and Soares-da-Silva, 2002).…”

Section: Discussionmentioning

confidence: 99%

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

et al. 2002

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Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) is a ubiquitous enzyme in nature that plays an important role in the metabolism of catechol neurotransmitters and xenobiotics. In particular, inactivation of drugs such as L-3,4-dihydroxyphenylalanine (L-DOPA) via O-methylation is of relevant pharmacological importance, because L-DOPA is currently the most effective drug used in the treatment of Parkinson's disease. This justified the interest in developing COMT inhibitors as potential adjuncts to L-DOPA therapy. The kinetics of inhibition by BIA 3-335 (1-[3,4-dihydroxy-5-nitrophenyl]-3-(N-3Ј-trifluormethylphenyl)-piperazine-1-propanone dihydrochloride) were characterized using recombinant rat soluble COMT. BIA 3-335 was found to act as a potent, reversible, tight-binding inhibitor of COMT with a K i of 6.0 Ϯ 1.6 nM and displaying a competitive inhibition toward the substrate binding site and uncompetitive inhibition toward the S-adenosyl-L-methionine (SAM) binding site. The 2.0-Å resolution crystal structure of COMT in complex with its cosubstrate SAM and a novel inhibitor BIA 3-335 shows the atomic interactions between the important residues at the active site and the inhibitor. This is the first report of a threedimensional structure determination of COMT complexed with a potent, reversible, and tight-binding inhibitor that is expected to have therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

et al. 2002

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“…The first series of bisubstrate inhibitors for COMT were designed and synthesized by Masjost et al on the basis of the enzyme's crystal structure and molecular docking [34]. Three binding pockets were defined: catechol pocket (for binding catechol), adenosine pocket (for binding the adenosine portion of the SAM cofactor) and methionine pocket (for binding the methionine portion of the SAM cofactor) (Figure 5A, B).The methionine pocket with a polar nature was not considered in the design of the bisubstrate inhibitor because it would be favourably filled with water [34]. Bisubstrate inhibitors should incorporate the adenosine and catechol portions that bind to the corresponding pockets ( Figure 5A, B).…”

Section: Bisubstrate Inhibitorsmentioning

confidence: 99%

Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders

2014

Br J Clin Pharmacol

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Catechol-O-methyltransferase (COMT) is of great importance in pharmacology because it catalyzes the metabolism (methylation) of endogenous and xenobiotic catechols. Moreover, inhibition of COMT is the drug target in the management of central nervous system (CNS) disorders such as Parkinson's disease due to its role in regulation of the dopamine level in the brain. The X-ray crystal structures for COMT have been available since 1994. The active sites for cofactor and substrate/inhibitor binding are well resolved to an atomic level, providing valuable insights into the catalytic mechanisms as well as the role of magnesium ions in catalysis. Determination of how the substrates/inhibitors bind to the protein leads to a structure-based approach that has resulted in potent and selective inhibitors. This review focuses on the design of two types of inhibitors (nitrocatechol-type and bisubstrate inhibitors) for COMT using the protein structures.

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“…Assuming that these compounds are all competitive inhibitors of SAM binding, the IC 50 data (Table 7) indicate that 5TA and MTA are rather poor PRMT1 inhibitors (K i > 80 μM based on Dixon analysis). These results were somewhat surprising, given that the S-adenosyl moiety has been used to generate high affinity bisubstrate analogues for catechol O-methyltransferase (57,58), and additionally calls into question the use of MTA as an in vivo inhibitor of PRMT1 activity (21). While MTA and 5TA are relatively poor PRMT1 inhibitors, the IC 50 obtained with homocysteine is significantly lower.…”

Section: Inhibition Studiesmentioning

confidence: 99%

Protein Arginine Methyltransferase 1: Positively Charged Residues in Substrate Peptides Distal to the Site of Methylation Are Important for Substrate Binding and Catalysis

et al. 2007

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Protein arginine methyltransferases (PRMTs) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., histones H3 and H4), and their activities influence a wide range of cellular processes, including cell growth, RNA splicing, differentiation, and transcriptional regulation. Dysregulation of these enzymes has been linked to heart disease and cancer, suggesting this enzyme family as a novel therapeutic target. To aid the development of PRMT inhibitors, we characterized the substrate specificity of both the rat and human PRMT1 orthologues using histone based peptide substrates. N-and C-terminal truncations to identify a minimal peptide substrate indicate that long-range interactions between enzyme and substrate are important for high rates of substrate capture. The importance of these long-range interactions to substrate capture were confirmed by "mutagenesis" experiments on a minimal peptide substrate. Inhibition studies on Sadenosyl-homocysteine, thioadenosine, methylthioadenosine, homocysteine, and sinefungin suggest that potent and selective bisubstrate analogue inhibitor(s) for PRMT1 can be developed by linking a histone based peptide substrate to homocysteine or sinefungin. Additionally, we present evidence that PRMT1 utilizes a partially processive mechanism to dimethylate its substrates.The protein arginine methyltransferases (PRMTs 1 ) are a group of evolutionarily conserved Sadenosyl-L-methionine (SAM)-dependent enzymes that catalyze the direct transfer of a methyl group from SAM to one or more of the η-nitrogens of an Arg residue. This is an S N 2 type reaction, and at least three products are possible, i.e., monomethyl Arg (MMA), asymmetric dimethyl Arg (ADMA), and symmetric dimethyl Arg (SDMA) (Figure 1). The PRMTs are generally classified as either type I or type II enzymes; type I PRMTs catalyze the formation †

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Structure-Based Design, Synthesis, and in vitro Evaluation of Bisubstrate Inhibitors for CatecholO-Methyltransferase (COMT)

Cited by 62 publications

References 19 publications

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

Kinetics and Crystal Structure of Catechol-O-Methyltransferase Complex with Co-Substrate and a Novel Inhibitor with Potential Therapeutic Application

Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders

Protein Arginine Methyltransferase 1: Positively Charged Residues in Substrate Peptides Distal to the Site of Methylation Are Important for Substrate Binding and Catalysis

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