5K0C

Crystal Structure of COMT in complex with 2,4-dimethyl-5-[3-(2-phenylpropan-2-yl)-1H-pyrazol-5-yl]-1,3-thiazole

Summary for 5K0C

• Entry DOI: 10.2210/pdb5k0c/pdb
• Descriptor: Catechol O-methyltransferase, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: methyltransferase, neurotransmitter degradation, catechol, transferase
• Biological source: Rattus norvegicus (Norway Rat)
• Total number of polymer chains: 2
• Total formula weight: 49320.57

Authors

Ehler, A.,Rodriguez-Sarmiento, R.M.,Rudolph, M.G. (deposition date: 2016-05-17, release date: 2016-09-07, Last modification date: 2024-05-08)

Primary citation

Lerner, C.,Jakob-Roetne, R.,Buettelmann, B.,Ehler, A.,Rudolph, M.,Rodriguez Sarmiento, R.M.
Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket.
J. Med. Chem., 59:10163-10175, 2016

PubMed Abstract: A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.

PubMed: 27685665
DOI: 10.1021/acs.jmedchem.6b00927

Experimental method

X-RAY DIFFRACTION (1.95 Å)